替米沙坦中国人群的遗传药理学研究
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摘要
第一章药物转运蛋白基因的遗传多态性对替米沙坦药动学的影响
研究背景
替米沙坦(telmisartan)是一种血管紧张素Ⅱ(AngiontensinⅡ,AngⅡ)1型(AT1)受体拮抗药,具有高选择性、不可逆地拮抗AT_1受体,而不抑制血管紧张素转换酶,不影响缓激肽的效应;也不与其它激素受体和离子通道结合或产生阻断作用,因而不影响包括心血管调节在内的其它受体系统。近年来对替米沙坦研究的范围还涉及有心血管(心力衰竭、心肌肥厚、心肌梗死等)、内分泌(糖尿病等)、肾病(糖尿病肾病、蛋白尿等)和神经系统(脑卒中)等众多领域,其已成为近年来心血管领域研究的热点,倍受临床关注。替米沙坦的体内药物浓度及降压疗效存在很大的个体差异,而导致这种差异的原因目前尚不明确。
多种药物转运蛋白参与替米沙坦的吸收(Absorption)、分布(Distribution)、代谢(Metabolism)、排泄(Excretion)过程,且研究表明,多种编码药物转运蛋白的基因存在单核苷酸基因多态性,遗传因素所导致的药物转运蛋白活性的差异可能是导致替米沙坦血药浓度和药物反应性个体差异的原因之一。替米沙坦的体内过程主要受MDR1(多药耐药蛋白1,Multidrug resistance 1,又名P-gp)、MRP2(多药耐药相关蛋白2,Multidrug resistance-related protein 2)和OATP1B3(有机阴离子转运体1B3亚型,Organic anion transporters 1B3)药物转运蛋白的影响,而上述转运蛋白的基因多态性可影响各自底物的血药浓度及药代动力学。因此,本章我们从健康受试者及高血压患者两大人群出发,探讨上述三种转运蛋白的基因多态性是否影响替米沙坦在人体内的药代动力学特征及降压疗效。
方法
采用限制性片段长度内切酶(PCR-RFLP)的方法对60名中国健康男性志愿者的MDR1 C3435T、MRP2 G1249A、MRP2 C3972T、OATP1B3T334G和OATP1B3 G699A位点进行基因分型,从中挑选适合的基因型个体进行进一步的研究。
基因型符合要求的受试者按照40 mg的剂量单次口服替米沙坦片,并于服药前(0 h)及服药后0.25 h、0.5 h、0.75 h、1 h、1.5 h、2 h、3 h、4 h、6 h、8 h、10 h、12 h、24 h、48 h分别采集肘静脉血5 mL,分离血浆,采用HPLC-MS(High performance liquid chromatogram-mass spectrometry,高效液相色谱—质谱检测器)法测定受试者体内不同时间点血浆中替米沙坦的药物浓度。采用DAS 2.0软件计算替米沙坦的药代动力学参数,并使用SPSS 13.0软件包比较基因型组间替米沙坦的药动学参数。
选择符合1999年WHO/ISH诊断标准的原发性高血压病人,治疗前测定基础血压。按照每天一次,每次40 mg的给药剂量,连续服用替米沙坦片30天,测定治疗30天后的血压,采集第30天服药前血样,进行替米沙坦稳态血浆药物谷浓度的测定并对MDR1 C3435T、MRP2 C3972T、OATP1B3T334G和OATP1B3 G699A位点进行基因分型。采用HPLC-FLD法测定血浆中替米沙坦的浓度,使用SPSS 13.0软件包比较基因型组间替米沙坦的稳态谷浓度及疗效间的差异。
结果
MDR1 C3435T、MRP2 G1249A、MRP2 C3972T、OATP1B3 T334G和OATP1B3 G699A位点的等位基因发生频率与文献报道及HapMap中报道的结果基本一致,其中OATP1B3 T334G和OATP1B3 G699A位点间呈完全连锁不平衡。
19位参加药动学研究的受试者,服药后替米沙坦的平均药动学参数T_(max)、C_(max)、t_(1/2)、AUC_(0-48)和AUC_(0-∞)分别为1.4±0.7 h(0.5～3.0 h)、312.7±279.7μg·L~(-1)(26.4～871.7μg·L~(-1))、13.9±8.1 h(2.5～38.9 h)、1477.4±927.4μg·h·L~(-1)(184.8～3134.0μg·h·L~(-1))和1662.3±1100.1μg·h·L~(-1)(194.7～3816.2μg·h·L~(-1))。个体间替米沙坦的上述药物代谢动力学参数问都存在很大的个体差异。经方差分析及独立样本t检验,替米沙坦的药动学参数在MDR1C3435T、MRP2 G1249A、MRP2 C3972T和OATP1B3 T334G/G699A位点不同基因型个体间均无显著性差异。
58位高血压患者治疗前后的血压分别为164/94 mmHg(SBP变化范围:220～130 mmHg;DBP变化范围:128～70 mmHg)和143/87 mmHg(SBP变化范围:194～110 mmHg;DBP变化范围:110～65 mmHg),服用替米沙坦30天后,其血浆中药物稳态谷浓度为50.10±6.95μg·L~(-1)(波动范围:0.34μg·L~(-1)～258.42μg·L~(-1)),个体间的药物血药浓度同样存在很大的个体差异。经统计学分析,MDR1 C3435T、MRP2 C3972T、OATP1B3T334G/OATP1B3 G699A基因多态性对替米沙坦的稳态谷浓度变化没有影响。MRP2 C3972T基因多态性与治疗前后收缩压的变化值有关,基因型为3972TT的个体表现出更好的降压效果。
结论
MDR1 C3435T、MRP2 G1249A、MRP2 C3972T、OATP1B3 T334G/G699A位点的基因多态性不影响健康中国男性志愿者替米沙坦的药物代谢动力学。MDR1 C3435T、MRP2 C3972T、OATP1B3 T334G/OATP1B3G699A基因多态性与高血压患者替米沙坦的稳态谷浓度间无相关性,但MRP2 C3972T多态可以影响替米沙坦降低收缩压的作用程度。
第二章SIRT1和DDAH1基因的遗传多态性对中国人替米沙坦降压疗效的影响
研究背景
高血压病是近半个世纪以来影响人类健康和生活质量、导致人类死亡的重要疾病之一。替米沙坦是AT_1受体阻断剂,临床上广泛应用于高血压病的治疗。研究发现在不同人种中,替米沙坦对轻、中度高血压治疗的有效率约为52%-56%,且其降压疗效存在很大的个体差异,大量的患者在使用替米沙坦单一药物进行治疗时需要加大剂量或联合使用其他降压药物。然而到目前为止,导致这种显著地药物反应性个体差异的原因仍尚不明确。
随着对替米沙坦药理作用研究的不断深入,人们发现替米沙坦除具有降压作用外,还具有改善胰岛素抵抗和糖、脂代谢紊乱,及抗动脉粥样硬化的作用,上述作用可能与替米沙坦增加PPAR-γ(Peroxisome proliferatoractivated receptor-γ,过氧化物酶体增生物激活受体-γ)蛋白表达、上调DDAH(Dimethylarginine dimethylaminohydrolase,二甲基精氨酸二甲氨水解酶)表达和降低ADMA(Asymmetric dimethylarginine,非对称性二甲基精氨酸)浓度有关。SIRT1属于沉默信息调节因子2(Sir2)家族成员,该蛋白家族的活性依赖于烟酰胺腺嘌呤二核昔酸(NAD~+)的去乙酰化酶,其在调节基因表达、细胞凋亡、代谢和老化过程中发挥重要作用。有研究发现AT1受体基因的近侧启动子区(-61bp到+25bp)包含SP1结合位点,SIRT1能够抑制SP1结合到AT1受体基因启动子上,从而下调AT1受体的表达,进而影响AngⅡ发挥缩血管效应,因此我们推测,DDAH1和SIRT1基因的遗传多态性可能在受体后水平影响替米沙坦的降压疗效。
本研究从药物作用受体后信号通路蛋白出发,研究SIRT1和DDAH1基因的遗传多态性对替米沙坦降压疗效的影响,从而寻找影响替米沙坦降压疗效的SNP,为临床合理应用替米沙坦进行降压治疗提供指导。
方法
原发性高血压患者58例,应用题米沙坦治疗前测量基础血压,并抽取5 ml肘静脉血,分离血浆用于测定基础状态ADMA的浓度,血细胞用于DNA的提取。入组的病人按照每天一次、每次40 mg的给药剂量,连续服用替米沙坦30天。试验第31天服药前测量治疗后血压,并抽取肘静脉血7 ml,用于治疗后ADMA浓度的测定。
采用PCR-RFLP法对DDAH1 C143611G、DDAH1 C144563T和SIRT1C-1138T位点进行基因分型;使用HPLC-MS法测定治疗前后血浆中ADMA的浓度。
使用SPSS 13.0软件包选取适当的统计学方法对替米沙坦的降压疗效及治疗前后ADMA水平的变化情况进行基因型组间的比较。
结果
高血压患者中DDAH1 C143611G、DDAH1 C144563T和SIRT1C-1138T位点的等位基因频率及基因型与HapMap中报道的中国北京人群的基因分布特征一致。
58例高血压患者完成了本项研究,治疗前患者血浆中ADMA的浓度为0.355±0.014μmol·L~(-1)(波动范围:0.632μmol·L~(-1)～0.106μmol·L~(-1))。按照每天给药一次,每次40 mg的剂量,连续服用替米沙坦片30天后,其血浆中ADMA的浓度为0.455±0.020μmol·L~(-1)(波动范围:0.759μmol·L~(-1)～0.140μmol·L~(-1)),其中14例患者治疗后血浆ADMA的浓度降低,44例患者治疗后血浆ADMA的浓度升高,治疗前后血浆ADMA的浓度存在显著的差异(p＜0.001)。
DDAH1 C143611G多态与替米沙坦的降压疗效无关,但DDAH1C144563T多态与替米沙坦治疗前后收缩压(SBP)和舒张压(DBP)的改变程度有关;SIRT1 C-1138T多态与舒张压的变化程度有关。
结论
DDAH1 C144563T及SIRT1 C-1138T多态可影响替米沙坦的降压疗效。
Chapter 1 The polymorphisms of drug transporters on the effect of telmisartan pharmacokinetics
Background
Telmisartan is an angiotensinⅡreceptor antagonist,can high selectively and irreversibly antagonize AT1 receptor,but don't inhibit the angiotensin-converting enzyme or affect the effects of bradykinin.It also does not bind or block other hormone receptors or ion channels,therefore does not affect the other receptor systems including the cardiovascular condition system.In recent years,much evdences has shown that,,beside the effect on decrease the blood pressure,telmisartan also has the effects on other cardiovascular disease,endocrine diseases,nephropathy and diseases of the nervous system.The basis for the remarkable interindividual differences in the plasma concentration and response of telmisartan remains unknown.
Several drug transporters are involved in the ADME process of telmisartan.Pharmacogenetics studies have shown that genes encoding drug transporters have a variety of single nucleotide polymorphisms(SNP).Genetic factors that affect the activity of drug transporters may be one of the reasons for the individual differences in telmisartan plasma concentration and drug response.There are three main drug transporters impact the process of telmisartan in vivo,MDR1(P-gp),MRP2 and OATP1B3.The polymorphisms of the genes can affect the pharmacokinetics of their own substrates.Therefore, in our researches,we investigated genetic polymorphisms of these three drug transporters on the effect of telmisartan pharmacokinetics in healthy volunteers and the steady-state concentration or treatment in hypertensive patients.
Methods
Genotyping of the MDR1 C3435T,MRP2 G1249A,MRP2 C3972T, OATP1B3 T334G and OATP1B3 G699A polymorphism were performed by using method of polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP).Sixty unrelated male volunteers were enrolled and screened for their MDR1 C3435T genotypes,and were selected for participation in the further study.
The subjects,whose genotype fit the requirements,received a single oral dose of 40 mg telmisartan.Venous blood samples of 5 mL were drawn from forearm vein into EDTA tubes before(0 h) and at 0.25,0.5,0.75,1,1.5,2,3,4, 6,8,10,12,24,and 48h,respectively,after telmisartan administration.Plasma was separated,and determined by high performance liquid chromatogrammass spectrometry(HPLC-MS).The pharmacokinetics of telmisartan was analyzed with DAS 2.0 software.Statistical analyses were performed by the SPSS 13.0 software for Windows.
Essential hypertension patients were requested to measure the basis blood pressure before telmisartan therapy.All the patients were treated with telmisartan for 30 days,according to once a day,40 mg per time in every morning.Blood pressure was measured in the thirty-first days,and venous blood samples were collected before telmisartan administration.The plasma was used to determine the concentration of telmisartan and whole blood was used to analyze the genotypes of MDR1 C3435T,MRP2 C3972T,OATP1B3 T334G and OATP1B3 G699A,respectively.The plasma concentration of telmisartan was determined by high performance liquid chromatogram-fluorescence detector(HPLC-FLD).Statistical analyses were performed by the SPSS 13.0 software for Windows.
Results
The allelic frequencies and genotype distribution of MDR1 C3435T, MRP2 G1249A,MRP2 C3972T,OATP1B3 T334G and OATP1B3 G699A were not different from those reported in Chinese.OATP1B3 T334G and OATP1B3 G699Apolymorphisms are in complete linkage disequilibrium.
Mean±SD and variation of T_(max),C_(max),t_(1/2),AUC_(0-48) and AUC_(0-∞) of 40 mg orally administrated telmisartan were 1.4±0.7 h(0.5～3.0 h),312.7±279.7μg·L~(-1)(26.4～871.7μg·L~(-1)),13.9±8.1 h(2.5～38.9 h),1477.4±927.4μg·h·L~(-1) (184.8～3134.0μg·h·L~(-1)) and 1662.3±1100.1μg·h·L~(-1)(194.7～3816.2μg·h·L~(-1)), respectively,in the overall 19 cases of subjects.There are significant individual differences in the pharmacokinetics of telmisartan.
The blood pressure of 58 cases of essential hypertensive patients before and after telmisartan therapy were 164/94 mmHg(range:220～130 mmHg for SBP;128～70 mmHg for DBP) and 143/87 mmHg(range:194～110 mmHg for SBP;110～65 mmHg for DBP) respectively.There was also significant individual difference in the concentration of telmisartan.Statistical analysis showed that the polymorphism of MDR1 C3435T,MRP2 C3972T,OATP1B3 T334G/OATP1B3 G699A were not associated with plasma steady-state concentration of telmisartan.MRP2 C3972T polymorphism affected ASBP with telmisartan therapy,individuals with the 3972TT genotype showed significantly higher degree of decrease in SBP after telmisartan therapy.
Conclusion
We found that the MDR1 C3435T、MRP2 G1249A、MRP2 C3972T、OATP1B3 T334G and OATP1B3 G699A polymorphism were not associated with the pharmacokinetics parameters of telmisartan in this study.The genetic polymorphisms of MDR1 C3435T,MRP2 C3972T,OATP1B3 T334G/OATP 1B3 G699A were not associated with telmisartan steady-state concentration, MRP2 C3972T polymorphism affectedΔSBP with telmisartan therapy.
Chapter 2 Effect of genetic polymorphisms in SIRT1 and DDAH1 on antihypertensive efficacy of telmisartan in a Chinese population
Background
Hypertension is an important disease which affecting human health and quality of life since the nearly half a century.Telmisartan is an angiotensinⅡreceptor antagonist;it is widely used in clinical treatment of hypertension. Evidence has shown that the response rate of telmisartan ranged from 52%to 56%in mild-to-moderate hypertension in patients with different ethnic backgrounds.A considerable percentage of patients also need dose titration during hypertension monotherapy.The basis for the remarkable interindividual difference in telmisartan response remains unknown.
With the deep researches on the pharmacological effects of telmisartan, scientists found that telmisartan can increase the expression of PPAR-γ, reduce the expression of DDAH(Dimethylarginine dimethylaminohydrolase) and increase the concentration of the endogenous NO synthase inhibitor-ADMA (Asymmetric dimethylarginine).Therefore,telmisartan can not only decrease the BP,but also improve insulin resistance and glucose-lipid metabolism disorders,and have the antiatherogenic role.SIRT1 is one of silent information regulator 2(SIR2).Sirtuins require nicotinamide adenine dinucleotide(NAD~+) as a cosubstrate for the deacetylation reaction,and they are highly preserved among numerous species and are associated with longevity,cell cycle regulation,apoptosis,DNA damage repair,and muscle differentiation.Deletion analysis of the AT_1R gene promoter revealed that suppression of AT_1R expression by resveratrol,a well known SIRT1 activator, is dependent on the most proximal promoter region(from -61 bp to -25 bp), which contains Sp1 binding site(GC box),the data suggested that resveratrol inhibits Sp1 binding to AT1R gene promoter and AT_1R gene transcription, induced AT_1R downregulation.We,therefore,hypothesized that the polymorphism of DDAH1 and SIRT1 maybe affect the treatment of telmisartan in the level of post-receptor.
In this part of our researches,we focus on whether the DDAH1 and SIRT1 genetic polymorphisms may affect the antihypertensive efficacy of telmisartan,in order to find the SNPs which can impact the response of telmisartan,and provide guidance for the clinical application of telmisartan.
Methods
Essential hypertension patients were requested to measure the basic blood pressure,and collected 5 mL blood samples.The plasma was used to detect the concentration of ADMA,and the blood cell was used to extract DNA. Patients were treated with telmisartan for 30 days,according to once a day,40 mg per time in the morning.Measure the blood pressure in the 31th days,and 7 mL blood samples were collected before telmisartan administration.The plasma was used to determine the concentration of ADMA.
Genotype of the DDAH1 C143611G、DDAH1 C144563T and SIRT1 C-1138T polymorphism were performed by using method of polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP).The plasma concentration of ADMA was determined by high performance liquid chromatogram-mass spectrometry(HPLC-MS).Statistical analyses were performed by the SPSS 13.0 software for Windows.
Results
The genotype and allele frequencies distribution characteristics of DDAH1 C143611G,DDAH1 C144563T and SIRT1 C-1138T were the same as the results reported in HapMap.
58 cases of patients had finished the study.The mean concentration of ADMA was 0.355±0.014μmol·L~(-1)(range from 0.632μmol·L~(-1) to 0.106μmol·L~(-1)) before treatment,and 0.455±0.020μmol·L~(-1)(range from 0.759μmol·L~(-1) to 0.140μmol·L~(-1)) after 30-day therapy treatment.Fourteen EH cases showed decreased plasma concentration of ADMA after telmisartan treatment, while 44 EH cases showed increased plasma concentration of ADMA after telmisartan treatment.Significant differences in plasma concentration of before and after telmisartan treatment was observed(p＜0.001).
Significant difference inΔSBP andΔDBP was observed among individuals with different genotypes of DDAH1 C144563T polymorphism. Significant difference inΔDBP was also observed among individuals with different genotypes of SIRT1 C-1138T polymorphism.No association was observed between DDAH1 C143611G polymorphism and the hypotensive effect of telmisartan.
Conclusion
DDAH1 C144563T and SIRT1 C-1138T polymorphism may affect the anti-hypertensive efficacy of telmisartan in Chinese population.
研究背景
替米沙坦(telmisartan)是一种血管紧张素Ⅱ(AngiontensinⅡ,AngⅡ)1型(AT1)受体拮抗药,具有高选择性、不可逆地拮抗AT_1受体,而不抑制血管紧张素转换酶,不影响缓激肽的效应;也不与其它激素受体和离子通道结合或产生阻断作用,因而不影响包括心血管调节在内的其它受体系统。近年来对替米沙坦研究的范围还涉及有心血管(心力衰竭、心肌肥厚、心肌梗死等)、内分泌(糖尿病等)、肾病(糖尿病肾病、蛋白尿等)和神经系统(脑卒中)等众多领域,其已成为近年来心血管领域研究的热点,倍受临床关注。替米沙坦的体内药物浓度及降压疗效存在很大的个体差异,而导致这种差异的原因目前尚不明确。
多种药物转运蛋白参与替米沙坦的吸收(Absorption)、分布(Distribution)、代谢(Metabolism)、排泄(Excretion)过程,且研究表明,多种编码药物转运蛋白的基因存在单核苷酸基因多态性,遗传因素所导致的药物转运蛋白活性的差异可能是导致替米沙坦血药浓度和药物反应性个体差异的原因之一。替米沙坦的体内过程主要受MDR1(多药耐药蛋白1,Multidrug resistance 1,又名P-gp)、MRP2(多药耐药相关蛋白2,Multidrug resistance-related protein 2)和OATP1B3(有机阴离子转运体1B3亚型,Organic anion transporters 1B3)药物转运蛋白的影响,而上述转运蛋白的基因多态性可影响各自底物的血药浓度及药代动力学。因此,本章我们从健康受试者及高血压患者两大人群出发,探讨上述三种转运蛋白的基因多态性是否影响替米沙坦在人体内的药代动力学特征及降压疗效。
方法
采用限制性片段长度内切酶(PCR-RFLP)的方法对60名中国健康男性志愿者的MDR1 C3435T、MRP2 G1249A、MRP2 C3972T、OATP1B3T334G和OATP1B3 G699A位点进行基因分型,从中挑选适合的基因型个体进行进一步的研究。
基因型符合要求的受试者按照40 mg的剂量单次口服替米沙坦片,并于服药前(0 h)及服药后0.25 h、0.5 h、0.75 h、1 h、1.5 h、2 h、3 h、4 h、6 h、8 h、10 h、12 h、24 h、48 h分别采集肘静脉血5 mL,分离血浆,采用HPLC-MS(High performance liquid chromatogram-mass spectrometry,高效液相色谱—质谱检测器)法测定受试者体内不同时间点血浆中替米沙坦的药物浓度。采用DAS 2.0软件计算替米沙坦的药代动力学参数,并使用SPSS 13.0软件包比较基因型组间替米沙坦的药动学参数。
选择符合1999年WHO/ISH诊断标准的原发性高血压病人,治疗前测定基础血压。按照每天一次,每次40 mg的给药剂量,连续服用替米沙坦片30天,测定治疗30天后的血压,采集第30天服药前血样,进行替米沙坦稳态血浆药物谷浓度的测定并对MDR1 C3435T、MRP2 C3972T、OATP1B3T334G和OATP1B3 G699A位点进行基因分型。采用HPLC-FLD法测定血浆中替米沙坦的浓度,使用SPSS 13.0软件包比较基因型组间替米沙坦的稳态谷浓度及疗效间的差异。
结果
MDR1 C3435T、MRP2 G1249A、MRP2 C3972T、OATP1B3 T334G和OATP1B3 G699A位点的等位基因发生频率与文献报道及HapMap中报道的结果基本一致,其中OATP1B3 T334G和OATP1B3 G699A位点间呈完全连锁不平衡。
19位参加药动学研究的受试者,服药后替米沙坦的平均药动学参数T_(max)、C_(max)、t_(1/2)、AUC_(0-48)和AUC_(0-∞)分别为1.4±0.7 h(0.5～3.0 h)、312.7±279.7μg·L~(-1)(26.4～871.7μg·L~(-1))、13.9±8.1 h(2.5～38.9 h)、1477.4±927.4μg·h·L~(-1)(184.8～3134.0μg·h·L~(-1))和1662.3±1100.1μg·h·L~(-1)(194.7～3816.2μg·h·L~(-1))。个体间替米沙坦的上述药物代谢动力学参数问都存在很大的个体差异。经方差分析及独立样本t检验,替米沙坦的药动学参数在MDR1C3435T、MRP2 G1249A、MRP2 C3972T和OATP1B3 T334G/G699A位点不同基因型个体间均无显著性差异。
58位高血压患者治疗前后的血压分别为164/94 mmHg(SBP变化范围:220～130 mmHg;DBP变化范围:128～70 mmHg)和143/87 mmHg(SBP变化范围:194～110 mmHg;DBP变化范围:110～65 mmHg),服用替米沙坦30天后,其血浆中药物稳态谷浓度为50.10±6.95μg·L~(-1)(波动范围:0.34μg·L~(-1)～258.42μg·L~(-1)),个体间的药物血药浓度同样存在很大的个体差异。经统计学分析,MDR1 C3435T、MRP2 C3972T、OATP1B3T334G/OATP1B3 G699A基因多态性对替米沙坦的稳态谷浓度变化没有影响。MRP2 C3972T基因多态性与治疗前后收缩压的变化值有关,基因型为3972TT的个体表现出更好的降压效果。
结论
MDR1 C3435T、MRP2 G1249A、MRP2 C3972T、OATP1B3 T334G/G699A位点的基因多态性不影响健康中国男性志愿者替米沙坦的药物代谢动力学。MDR1 C3435T、MRP2 C3972T、OATP1B3 T334G/OATP1B3G699A基因多态性与高血压患者替米沙坦的稳态谷浓度间无相关性,但MRP2 C3972T多态可以影响替米沙坦降低收缩压的作用程度。
第二章SIRT1和DDAH1基因的遗传多态性对中国人替米沙坦降压疗效的影响
研究背景
高血压病是近半个世纪以来影响人类健康和生活质量、导致人类死亡的重要疾病之一。替米沙坦是AT_1受体阻断剂,临床上广泛应用于高血压病的治疗。研究发现在不同人种中,替米沙坦对轻、中度高血压治疗的有效率约为52%-56%,且其降压疗效存在很大的个体差异,大量的患者在使用替米沙坦单一药物进行治疗时需要加大剂量或联合使用其他降压药物。然而到目前为止,导致这种显著地药物反应性个体差异的原因仍尚不明确。
随着对替米沙坦药理作用研究的不断深入,人们发现替米沙坦除具有降压作用外,还具有改善胰岛素抵抗和糖、脂代谢紊乱,及抗动脉粥样硬化的作用,上述作用可能与替米沙坦增加PPAR-γ(Peroxisome proliferatoractivated receptor-γ,过氧化物酶体增生物激活受体-γ)蛋白表达、上调DDAH(Dimethylarginine dimethylaminohydrolase,二甲基精氨酸二甲氨水解酶)表达和降低ADMA(Asymmetric dimethylarginine,非对称性二甲基精氨酸)浓度有关。SIRT1属于沉默信息调节因子2(Sir2)家族成员,该蛋白家族的活性依赖于烟酰胺腺嘌呤二核昔酸(NAD~+)的去乙酰化酶,其在调节基因表达、细胞凋亡、代谢和老化过程中发挥重要作用。有研究发现AT1受体基因的近侧启动子区(-61bp到+25bp)包含SP1结合位点,SIRT1能够抑制SP1结合到AT1受体基因启动子上,从而下调AT1受体的表达,进而影响AngⅡ发挥缩血管效应,因此我们推测,DDAH1和SIRT1基因的遗传多态性可能在受体后水平影响替米沙坦的降压疗效。
本研究从药物作用受体后信号通路蛋白出发,研究SIRT1和DDAH1基因的遗传多态性对替米沙坦降压疗效的影响,从而寻找影响替米沙坦降压疗效的SNP,为临床合理应用替米沙坦进行降压治疗提供指导。
方法
原发性高血压患者58例,应用题米沙坦治疗前测量基础血压,并抽取5 ml肘静脉血,分离血浆用于测定基础状态ADMA的浓度,血细胞用于DNA的提取。入组的病人按照每天一次、每次40 mg的给药剂量,连续服用替米沙坦30天。试验第31天服药前测量治疗后血压,并抽取肘静脉血7 ml,用于治疗后ADMA浓度的测定。
采用PCR-RFLP法对DDAH1 C143611G、DDAH1 C144563T和SIRT1C-1138T位点进行基因分型;使用HPLC-MS法测定治疗前后血浆中ADMA的浓度。
使用SPSS 13.0软件包选取适当的统计学方法对替米沙坦的降压疗效及治疗前后ADMA水平的变化情况进行基因型组间的比较。
结果
高血压患者中DDAH1 C143611G、DDAH1 C144563T和SIRT1C-1138T位点的等位基因频率及基因型与HapMap中报道的中国北京人群的基因分布特征一致。
58例高血压患者完成了本项研究,治疗前患者血浆中ADMA的浓度为0.355±0.014μmol·L~(-1)(波动范围:0.632μmol·L~(-1)～0.106μmol·L~(-1))。按照每天给药一次,每次40 mg的剂量,连续服用替米沙坦片30天后,其血浆中ADMA的浓度为0.455±0.020μmol·L~(-1)(波动范围:0.759μmol·L~(-1)～0.140μmol·L~(-1)),其中14例患者治疗后血浆ADMA的浓度降低,44例患者治疗后血浆ADMA的浓度升高,治疗前后血浆ADMA的浓度存在显著的差异(p＜0.001)。
DDAH1 C143611G多态与替米沙坦的降压疗效无关,但DDAH1C144563T多态与替米沙坦治疗前后收缩压(SBP)和舒张压(DBP)的改变程度有关;SIRT1 C-1138T多态与舒张压的变化程度有关。
结论
DDAH1 C144563T及SIRT1 C-1138T多态可影响替米沙坦的降压疗效。
Chapter 1 The polymorphisms of drug transporters on the effect of telmisartan pharmacokinetics
Background
Telmisartan is an angiotensinⅡreceptor antagonist,can high selectively and irreversibly antagonize AT1 receptor,but don't inhibit the angiotensin-converting enzyme or affect the effects of bradykinin.It also does not bind or block other hormone receptors or ion channels,therefore does not affect the other receptor systems including the cardiovascular condition system.In recent years,much evdences has shown that,,beside the effect on decrease the blood pressure,telmisartan also has the effects on other cardiovascular disease,endocrine diseases,nephropathy and diseases of the nervous system.The basis for the remarkable interindividual differences in the plasma concentration and response of telmisartan remains unknown.
Several drug transporters are involved in the ADME process of telmisartan.Pharmacogenetics studies have shown that genes encoding drug transporters have a variety of single nucleotide polymorphisms(SNP).Genetic factors that affect the activity of drug transporters may be one of the reasons for the individual differences in telmisartan plasma concentration and drug response.There are three main drug transporters impact the process of telmisartan in vivo,MDR1(P-gp),MRP2 and OATP1B3.The polymorphisms of the genes can affect the pharmacokinetics of their own substrates.Therefore, in our researches,we investigated genetic polymorphisms of these three drug transporters on the effect of telmisartan pharmacokinetics in healthy volunteers and the steady-state concentration or treatment in hypertensive patients.
Methods
Genotyping of the MDR1 C3435T,MRP2 G1249A,MRP2 C3972T, OATP1B3 T334G and OATP1B3 G699A polymorphism were performed by using method of polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP).Sixty unrelated male volunteers were enrolled and screened for their MDR1 C3435T genotypes,and were selected for participation in the further study.
The subjects,whose genotype fit the requirements,received a single oral dose of 40 mg telmisartan.Venous blood samples of 5 mL were drawn from forearm vein into EDTA tubes before(0 h) and at 0.25,0.5,0.75,1,1.5,2,3,4, 6,8,10,12,24,and 48h,respectively,after telmisartan administration.Plasma was separated,and determined by high performance liquid chromatogrammass spectrometry(HPLC-MS).The pharmacokinetics of telmisartan was analyzed with DAS 2.0 software.Statistical analyses were performed by the SPSS 13.0 software for Windows.
Essential hypertension patients were requested to measure the basis blood pressure before telmisartan therapy.All the patients were treated with telmisartan for 30 days,according to once a day,40 mg per time in every morning.Blood pressure was measured in the thirty-first days,and venous blood samples were collected before telmisartan administration.The plasma was used to determine the concentration of telmisartan and whole blood was used to analyze the genotypes of MDR1 C3435T,MRP2 C3972T,OATP1B3 T334G and OATP1B3 G699A,respectively.The plasma concentration of telmisartan was determined by high performance liquid chromatogram-fluorescence detector(HPLC-FLD).Statistical analyses were performed by the SPSS 13.0 software for Windows.
Results
The allelic frequencies and genotype distribution of MDR1 C3435T, MRP2 G1249A,MRP2 C3972T,OATP1B3 T334G and OATP1B3 G699A were not different from those reported in Chinese.OATP1B3 T334G and OATP1B3 G699Apolymorphisms are in complete linkage disequilibrium.
Mean±SD and variation of T_(max),C_(max),t_(1/2),AUC_(0-48) and AUC_(0-∞) of 40 mg orally administrated telmisartan were 1.4±0.7 h(0.5～3.0 h),312.7±279.7μg·L~(-1)(26.4～871.7μg·L~(-1)),13.9±8.1 h(2.5～38.9 h),1477.4±927.4μg·h·L~(-1) (184.8～3134.0μg·h·L~(-1)) and 1662.3±1100.1μg·h·L~(-1)(194.7～3816.2μg·h·L~(-1)), respectively,in the overall 19 cases of subjects.There are significant individual differences in the pharmacokinetics of telmisartan.
The blood pressure of 58 cases of essential hypertensive patients before and after telmisartan therapy were 164/94 mmHg(range:220～130 mmHg for SBP;128～70 mmHg for DBP) and 143/87 mmHg(range:194～110 mmHg for SBP;110～65 mmHg for DBP) respectively.There was also significant individual difference in the concentration of telmisartan.Statistical analysis showed that the polymorphism of MDR1 C3435T,MRP2 C3972T,OATP1B3 T334G/OATP1B3 G699A were not associated with plasma steady-state concentration of telmisartan.MRP2 C3972T polymorphism affected ASBP with telmisartan therapy,individuals with the 3972TT genotype showed significantly higher degree of decrease in SBP after telmisartan therapy.
Conclusion
We found that the MDR1 C3435T、MRP2 G1249A、MRP2 C3972T、OATP1B3 T334G and OATP1B3 G699A polymorphism were not associated with the pharmacokinetics parameters of telmisartan in this study.The genetic polymorphisms of MDR1 C3435T,MRP2 C3972T,OATP1B3 T334G/OATP 1B3 G699A were not associated with telmisartan steady-state concentration, MRP2 C3972T polymorphism affectedΔSBP with telmisartan therapy.
Chapter 2 Effect of genetic polymorphisms in SIRT1 and DDAH1 on antihypertensive efficacy of telmisartan in a Chinese population
Background
Hypertension is an important disease which affecting human health and quality of life since the nearly half a century.Telmisartan is an angiotensinⅡreceptor antagonist;it is widely used in clinical treatment of hypertension. Evidence has shown that the response rate of telmisartan ranged from 52%to 56%in mild-to-moderate hypertension in patients with different ethnic backgrounds.A considerable percentage of patients also need dose titration during hypertension monotherapy.The basis for the remarkable interindividual difference in telmisartan response remains unknown.
With the deep researches on the pharmacological effects of telmisartan, scientists found that telmisartan can increase the expression of PPAR-γ, reduce the expression of DDAH(Dimethylarginine dimethylaminohydrolase) and increase the concentration of the endogenous NO synthase inhibitor-ADMA (Asymmetric dimethylarginine).Therefore,telmisartan can not only decrease the BP,but also improve insulin resistance and glucose-lipid metabolism disorders,and have the antiatherogenic role.SIRT1 is one of silent information regulator 2(SIR2).Sirtuins require nicotinamide adenine dinucleotide(NAD~+) as a cosubstrate for the deacetylation reaction,and they are highly preserved among numerous species and are associated with longevity,cell cycle regulation,apoptosis,DNA damage repair,and muscle differentiation.Deletion analysis of the AT_1R gene promoter revealed that suppression of AT_1R expression by resveratrol,a well known SIRT1 activator, is dependent on the most proximal promoter region(from -61 bp to -25 bp), which contains Sp1 binding site(GC box),the data suggested that resveratrol inhibits Sp1 binding to AT1R gene promoter and AT_1R gene transcription, induced AT_1R downregulation.We,therefore,hypothesized that the polymorphism of DDAH1 and SIRT1 maybe affect the treatment of telmisartan in the level of post-receptor.
In this part of our researches,we focus on whether the DDAH1 and SIRT1 genetic polymorphisms may affect the antihypertensive efficacy of telmisartan,in order to find the SNPs which can impact the response of telmisartan,and provide guidance for the clinical application of telmisartan.
Methods
Essential hypertension patients were requested to measure the basic blood pressure,and collected 5 mL blood samples.The plasma was used to detect the concentration of ADMA,and the blood cell was used to extract DNA. Patients were treated with telmisartan for 30 days,according to once a day,40 mg per time in the morning.Measure the blood pressure in the 31th days,and 7 mL blood samples were collected before telmisartan administration.The plasma was used to determine the concentration of ADMA.
Genotype of the DDAH1 C143611G、DDAH1 C144563T and SIRT1 C-1138T polymorphism were performed by using method of polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP).The plasma concentration of ADMA was determined by high performance liquid chromatogram-mass spectrometry(HPLC-MS).Statistical analyses were performed by the SPSS 13.0 software for Windows.
Results
The genotype and allele frequencies distribution characteristics of DDAH1 C143611G,DDAH1 C144563T and SIRT1 C-1138T were the same as the results reported in HapMap.
58 cases of patients had finished the study.The mean concentration of ADMA was 0.355±0.014μmol·L~(-1)(range from 0.632μmol·L~(-1) to 0.106μmol·L~(-1)) before treatment,and 0.455±0.020μmol·L~(-1)(range from 0.759μmol·L~(-1) to 0.140μmol·L~(-1)) after 30-day therapy treatment.Fourteen EH cases showed decreased plasma concentration of ADMA after telmisartan treatment, while 44 EH cases showed increased plasma concentration of ADMA after telmisartan treatment.Significant differences in plasma concentration of before and after telmisartan treatment was observed(p＜0.001).
Significant difference inΔSBP andΔDBP was observed among individuals with different genotypes of DDAH1 C144563T polymorphism. Significant difference inΔDBP was also observed among individuals with different genotypes of SIRT1 C-1138T polymorphism.No association was observed between DDAH1 C143611G polymorphism and the hypotensive effect of telmisartan.
Conclusion
DDAH1 C144563T and SIRT1 C-1138T polymorphism may affect the anti-hypertensive efficacy of telmisartan in Chinese population.
引文
[1]Schinkel AH,Jonker JW.Mammalian drug effiux transporters of the ATP binding cassette(ABC) family:an overview.Adv Drug Deliv Rev.2003;55(1):3229.
[2]Efferth T.The human ATP-binding cassette transporter genes:from the bench to the bedside.Curr Mol Med.2001;1:45-65.
[3]Ambudkar SV,Kimchi-Sarfaty C,Sauna ZE,et al.P-glycoprotein:from genomics to mechanism.Oncogene.2003;22:7468-7485.
[4]Almond LM,Edirisinghe D,Dalton M,et al.Intracellular and plasma pharmacokinetics of nevirapine in human immunodeficiency virus-infected individuals.Clin Pharmacol Ther.2005;78:132-142.
[5]Chang C,Bahadduri PM,Polli JE,et al.Rapid identification of P-glycoprotein substrates and inhibitors.Drug Metab Dispos.2006;34(12):1976-1984.
[6]沈杰,焦正,李中东,等.替米沙坦在Caco-2细胞模型中的体外转运研究[J].中国药学杂志.2006,41(21):1624-1627.
[7]Stangier J,Su CA,Hendriksm G,et al.The effect of TMS on the steady-state pharmacokinetics of digoxin in healthy male volunteers.J Clin Pharmacol.2000;40(12):1373-1379.
[8]Kim RB,Leake BF,Choo EF,et al.Identification of functionally variant MDR1 alleles among European Americans and African Americans.Clin Pharmacol Ther.2001;70:189-199.
[9]Hoffmeyer S,Burk O,von Richter O,et al.Functional polymorphisms of the human multidrug resistance gene:Multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo.Proc Natl Acad Sci.2000;97:3473-3478.
[10]Wang D,Sad(?)e W.Searching for polymorphisms that affect gene expression and mRNA processing:example ABCB1(MDR1).AAPS J.2006;8(3):E515-520.
[11]Aarnoudse AJ,Dieleman JP,Visser LE,et al.Common ATP-binding cassette B1variants are associated with increased digoxin serum concentration.Pharmacogenet Genomics.2008;18(4):299-305.
[12]Suzuki H,Sugiyama Y.Single nucleotide polymorphisms in multidrug resistance associated protein 2(MRP2/ABCC2):its impact on drug disposition.Adv Drug Deliv Rev.2002;54(10):1311-1331.
[13]Payen L,Sparfel L,Courtois A,et al.The drug efflux pump MRP2:regulation of expression in physiopathological situations and by endogenous and exogenous compounds. Cell Biol. Toxicol. 2002; 18: 221-233.
[14]Elferink RO, Groen AK. Genetic defects in hepatobiliary transport. Biochim. Biophys. Acta. 2002; 1586: 129-145.
[15]Borst P, Elferink RO. Mammalian ABC transporters in health and disease. Annu. Rev. Biochem. 2002; 71: 537-592.
[16]Keitel V, Kartenbeck J, Nies AT, et al. Impaired protein maturation of the conjugate export pump multidrug resistance protein 2 as a consequence of a deletion mutation in Dubin-Johnson syndrome. Hepatology. 2000; 32: 1317-1328.
[17] Hashimoto K, Uchiumi T, Konno T, et al. Trafficking and functional defects by utations of the ATP-binding domains in MRP2 in patients with Dubin-Johnson syndrome. Hepatology. 2002; 36: 1236-1245.
[18]Nishino A, Kato Y, Igarashi T, et al. Both cMOAT/MRP2 and Another Unknown Transporter(s) Are Responsible for the Biliary Excretion of Glucuronide Conjugate of the Nonpeptide Angiotensin II Antagonist, Telmisaltan. Drug Metab Dispos. 2000; 28(10): 1146-1148.
[19]Ito S, Ieiri I, Tanabe M, et al. Polymorphism of the ABC transporter genes, MDR1, MRP1 and MRP2/cMOAT, in healthy Japanese subjects. Pharmacogenetics. 2001; 11: 175-184.
[20]Itoda M, Saito Y, Soyama A, et al. Polymorphisms in the ABCC2 (cMOAT/MRP2) gene found in 72 established cell lines derived from Japanese individuals: an association between single nucleotide polymorphisms in the 50- untranslated region and exon 28. Drug Metab Dispos. 2002; 30: 363-364.
[21 ] Innocenti F, Undevia SD, Chen PX, et al. Pharmacogenetic analysis of interindividual irinotecan pharmacokinetic variability: Evidence for functional variant of ABCC2.Proc Am Soc Clin Oncol. 2004; 22: 2010.
[22]Konig J, Seithel A, Gradhand U, et al. Pharmacogenomics of human OATP transporters. Naunyn-Schmiedeberg's Arch Pharmacol. 2006; 372: 432-443.
[23]Konig J, Cui Y, Nies AT, et al. Localization and genomic organization of a new hepatocellular organic anion transporting polypeptide. J Biol Chem. 2000; 275: 23161-23168.
[24] Kullak-Ublick GA, Ismair MG, Stieger B, et al. Organic anion-transporting polypeptide B (OATP-B) and its functional comparison with three other OATPs of human liver. Gastroenterology. 2001; 120: 525-533.
[25]Vavricka SR, Van Montfoort J, Ha HR, et al. Interactions of rifamycin SV and rifampicin with organic anion uptake systems of human liver. Hepatology. 2002; 36:164-172.
[26]Hirano M, Maeda K, Shitara Y, et al. Contribution of OATP2 (OATP1B1) and OATP8 (OATP1B3) to the hepatic uptake of pitavastatin in humans. J Pharmacol Exp Ther 2004; 311: 139-146.
[27]Ismair MG, Stieger B, Cattori V, et al. Hepatic uptake of cholecystokinin octapeptide by organic anion-transporting polypeptides OATP4 and OATP8 of rat and human liver.Gastroenterology. 2001; 121: 1185-1190.
[28]Shimizu M, Fuse K, Okudaira K, et al. Contribution of OATP (organic anion- transporting polypeptide) family transporters to the hepatic uptake of fexofenadine in humans. Drug Metab Dispos. 2005; 33: 1477-1481.
[29]Ishiguro N, Maeda K, Kishimoto W, et al. Predominant contribution of OATP1B3 to the hepatic uptake of telmisartan, an angiotensin II receptor antagonist, in humans.Drug Metab Dispos. 2006; 34: 1109-1115.
[30]Letschert K, Keppler D, Konig J. Mutations in the SLCO1B3 gene affecting the substrate specificity of the hepatocellular uptake transporter OATP1B3 (OATP8).Pharmacogenetics. 2004; 14: 441-452.
[31]Masatomo M, Shigeru S, Kazuyuki I, et al. Influence of SLCO1B1, 1B3, 2B1 and ABCC2 genetic polymorphisms on mycophenolic acid pharmacokinetics in Japanese renal transplant recipients. Eur J Clin Pharmacol. 2007; 63: 1161-1169.
[32]Wienen W, Entzeroth M, van Meel JCA, et al. A review on telmisartan: a novel. long-acting angiotensin II-receptor antagonist. Cardiovascular drug reviews. 2000, 18:127-156.
[33]Stangier J, Schmid J, Turck D, et al. Absorption, metabolism, and excretion of intravenously and orally administered [14C] telmisartan in healthy volunteers. J Clin Pharmacol. 2000b; 40: 1312-1322.
[34] Stangier J, Su CA, Schondorfer G, et al. Pharmacokinetics and safety of intravenous and oral telmisartan 20 mg and 120 mg in subjects with hepatic impairment compared with healthy volunteers. J Clin Pharmacol. 2000a; 40: 1355-1364.
[35]Ishiguro N, Maeda K, Saito A, et al. Establishment of a set of double transfectants coexpressing organic anion transporting polypeptide 1B3 and hepatic efflux transporters for the characterization of the hepatobiliary transport of telmisartan acylglucuronide. Drug Metab Dispos. 2008; 36(4): 796-805.
[36] Giles TD, Bakris GL, Smith DH, et al. Defining the antihypertensive properties of the angiotensin receptor blocker telmisartan by a practice-based clinical trial. Am J Hypertens. 2003; 16(6): 460-466.
[37]Plavnik FL, Ribeiro AB. A multicenter, open-label study of the efficacy and safety of telmisartan in mild to moderate hypertensive patients. Arq Bras Cardiol. 2002; 79(4):339-350.
[3 8] Zhang P, Zhang Y, Chen X, et al. Pharmacokinetics of telmisartan in healthy Chinese subjects after oral administration of two dosage levels. Arzneimittelforschung. 2006;56(8): 569-573.
[39] Smith DH, Matzek KM, Kempthorne-Rawson J. Dose response and safety of telmisartan in patients with mild to moderate hypertension. J Clin Pharmacol. 2000; 40(12): 1380-1390.
[40]Tatami S, Sarashina A, Yamamura N, et al. Population pharmacokinetics of an angiotensinⅡ receptor antagonist, telmisartan, in healthy volunteers and hypertensive patients. Drug Metab Pharmacokinet. 2003; 18(3): 203-211.
[41]Callen DF, Baker E, Simmers RN, et al. Localization of the human multiple drug resistance gene, MDR1, to 7q21.1. Hum Genet. 1987; 77(2): 142-144.
[42]Chinn LW, Kroetz DL. ABCB1 pharmacogenetics: progress, pitfalls, and promise. Clin Pharmacol Then 2007; 81(2): 265-269.
[43] Li D, Zhand GL, Lou YQ, et al. Genetic polymorphisms in MDR1 and CYP3A5 and MDR1 haplotype in mainland Chinese Han, Uygur and Kazakh ethnic groups. J Clin Pharm Ther. 2007; 32: 89-95.
[44] Vicente J, Sinues B, Fanlo A, et al. Polymorphism C3435T of the MDR1 gene in Central Americans and Spaniards. Mol Biol Rep. 2008; 35(3): 473-478.
[45]Hirouchi M, Suzuki H, Itoda M, et al. Characterization of the Cellular Localization, Expression Level, and Function of SNP Variants of MRP2/ABCC. Pharmaceutical Research. 2004; 21(5): 742-748.
[46]Cascorbi I. Role of pharmacogenetics of ATP-binding cassette transporters in the pharmacokinetics of drugs. Pharmacol Ther. 2006; 112(2): 457-473.
[47]Haenisch S, Mossiaguine I, Siegmund W, et al. Frequency of single nucleotide polymorphisms in the MRP2 gene in healthy German subjects. Eur J Clin Pharmacol.2002; 58: S95.
[48]Iida A, Saito S, Sekine A, et al.Catalog of 258 single-nucleotide polymorphisms (SNPs) in genes encoding three organic anion transporters, three organic anion-transporting polypeptides, and three NADH:ubiquinone oxidoreductase flavoproteins. J Hum Genet. 200l;46(11):668-683.
[49]赵霞,许俊羽,刘文英.反相高效液相色谱法测定大鼠血浆中替米沙坦的浓度.中国药科大学学报.2003;34(3):247-248.
[50]武洁,冯芳,蒋娟娟,等.HPLC-MS法测定人血浆中替米沙坦及药代动力学研究.中国药科大学学报.2004;35(6):545-547.
[51]沈杰,焦正,李中东,等.HPLC荧光法测定人血浆中替米沙坦的浓度.药物分析杂志.2005;25(1):47-49.
[52]Loeuillet C,Weale M,Deutsch S,et al.Promoter polymorphisms and allelic imbalance in ABCB1 expression.Pharmacogenet Genomics.2007;17(11):951-959.
[53]Miura M,Satoh S,Inoue K,et al.Telmisartan pharmacokinetics in Japanese renal transplant recipients.Clin Chim Acta.2009;399(1-2):83-87.
[1]Michel MC,Bohner H,Koster J,et al.Safety of telmisartan in patients with arterial hypertension:an open-label observational study.Drug Saf.2004;27:335-344.
[2]柏瑾,诸骏仁,蔡绳,等.替米沙坦治疗轻中度高血压的临床疗效和安全性.中华心血管病杂志.2002;30:738-742.
[3]于海波,韩雅玲,王祖禄,等.替米沙坦降压疗效的临床研究.高血压杂志.2004;12(6):515-518.
[4]程澜.血管紧张素Ⅱ受体阻断剂替米沙坦改善糖、脂代谢及抗动脉粥样硬化的作用机制及应用进展血管病学进展.2008;29(3):494-496.
[5]Takaya T,Kawashima S,Shinohara M,et al.Angiotensin Ⅱ type 1 receptor blocker telmisartan suppresses superoxide production and reduces atherosclerotic lesion formation in apolipoprotein E-deficient mice.Atherosclerosis.2006;186:402-410.
[6]Giles TD,Bakris GL,Smith DH,et al.Defining the antihypertensive properties of the angiotensin receptor blocker telmisartan by a practice-based clinical trial.Am J Hypertens.2003;16(6):460-466.
[7]Plavnik FL,Ribeiro AB.A multicenter,open-label study of the efficacy and safety of telmisartan in mild to moderate hypertensive patients.Arq Bras Cardiol.2002;79(4):339-350.
[8]Redon J,Luque-Otero M,Martell N,et al.Investigators.Renin-angiotensin system gene polymorphisms:relationship with blood pressure and microalbuminuria in telmisartan-treated hypertensive patients.Pharmacogenomics J.2005;5(1):14-20.
[9]郭韶洁,赵秀丽,武峰,等.内皮型一氧化氮合酶基因G894T多态性与替米沙坦降压效果的相关性.首都医科大学学报.2007;28(1):107-109.
[10]Strahl BD,Allis CD.The language of covalent histone modifications.Nature.2000;403(6765):41-45.
[11]Bitterman KJ,Anderson RM,Cohen HY,et al.Inhibition of silencing and accelerated aging by nicotinamide,a putative negative regulator of yeast sir2 and human SIRT1.J Biol Chem.2002;277(47):45099-45107.
[12]Blander G,Guarente L.The Sir2 family of protein deacetylases(Review).Armu Rev Biochem.2004;73:417-35.
[13]Frye RA.Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins.Biochem Biophys Res Commun.2000;273(2):793-798.
[14]Frye RA.Characterization of five human cDNAs with homology to the yeast SIR2gene:Sir2-like proteins(sirtuins) metabolize NAD and may have protein ADP- ribosyltransferase activity. Biochem Biophys Res Commun. 1999; 260(1): 273-279.
[15]Luo J, Nikolaev AY, Imai S, et al. Negative control of p53 by Sir2alpha promotes cell survival under stress. Cell. 2001; 107(2): 137-148.
[16]Vaziri H, Dessain SK, Ng Eaton E, et al. hSIR2 (SIRT1) functions as an NAD- dependent p53 deacetylase. Cell. 2001; 107 (2): 149-159.
[17]Senawong T, Peterson VJ, Avram D, et al. Involvement of the histone deacetylase SIRT1 in chicken ovalbumin upstream promoter transcription factor (COUP-TF)- interacting protein 2-mediated transcriptional repression. J Biol Chem. 2003; 278(44):43041-43050.
[18]Takata T, Ishikawa FH. Sir2-related protein SIRT1 associates with the bHLH repressors HES1 and HEY2 and is involved in HES1-and HEY2-mediated transcriptional repression. Biochem Biophys Res Commun. 2003; 301(1): 250-257.
[19]Fulco M, Schiltz RL, Iezzi S, et al. Sir2 regulates skeletal muscle differentiation as a potential sensor of the redox state. Molecular Cell. 2003; 12: 51-62.
[20]Brunet A, Sweeney LB, Sturgill JF, et al. Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science. 2004; 303(5666): 2011-2015.
[21]Motta MC, Divecha N, Lemieux M, et al. Mammalian SIRT1 represses forkhead transcription factors. Cell. 2004; 16(4): 551-563.
[22]Picard F, Kurtev M, Chung N, et al. Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-gamma. Nature. 2004; 429(6993): 771-776.
[23] Yeung F, Hoberg JE, Ramsey CS, et al. Modulation of NF-kappaB-dependent transcription and cell survival by the SIRT1 deacetylase. EMBO J. 2004; 23(12): 2369-2380.
[24] Cohen HY, Miller C, Bitterman KJ, et al. Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. Science. 2004; 305(5682): 390-392.
[25]Chua KF, Mostoslavsky R, Lombard DB, et al. Mammalian SIRT1 limits replicative life span in response to chronic genotoxic stress. Cell metabolism. 2005; 2: 67-76.
[26]Kobayashi Y, Furukawa-Hibi Y, Chen C, et al. SIRT1 is critical regulator of FOXO-mediated transcription in response to oxidative stress. Int J Mol Med. 2005;16(2): 237-243.
[27] Zhou B, Wu LJ, Li LH, et al. Silibinin protects against isoproterenol-induced rat cardiac myocyte injury through mitochondrial pathway after up-regulation of SIRT1. J Pharmacol Sci. 2006; 102(4): 387-395.
[28]Alcendor RR, Gao S, Zhai P, et.al. Sirtl regulates aging and resistance to oxidative stress in the heart. Circ Res. 2007; 100(10): 1512-1521.
[29]Alcendor RR, Kirshenbaum LA, Imai S, et al. Silent information regulator 2alpha, a longevity factor and class Ⅲ histone deacetylase, is an essential endogenous apoptosis inhibitor in cardiac myocytes. Circ Res. 2004; 95(10): 971-980.
[30]Regula KM, Kirshenbaum LA. p53 activates the mitochondrial death pathway and apoptosis of ventricular myocytes independent of de novo gene transcription. J Mol Cell Cardiol. 2001; 33(8): 1435-1445.
[31] Miyazaki R, Ichiki T, Hashimoto T, et al. SIRT1, a longevity gene, downregulates angiotensinⅡ type 1 receptor expression in vascular smooth muscle cells. Arterioscler Thromb Vase Biol. 2008; 28(7): 1263-1269.
[32]Peeters AV, Beckers S, Verrijken A, et al. Association of SIRT1 gene variation with visceral obesity. Hum Genet. 2008; 124(4): 431-436.
[33]Helisalmi S, Vepsalainen S, Hiltunen M, et al. Genetic study between SIRT1, PPARD, PGC-1 alpha genes and Alzheimer's disease. J Neurol. 2008; 255(5): 668-73.
[34]Lagouge M, Argmann C, Gerhart-Hines Z, et al. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1 alpha. Cell. 2006; 127(6): 1109-22.
[35]Gokce N. L-arginine and hypertension. J Nutr. 2004; 134(10 Suppl 1): 2807S-2811S.
[36]Rudic RD, Shesely EG, Maeda N, et al. Direct evidence for the importance of endo- thelium-derived nitric oxide in vascular remodeling. J Clin Invest. 1998; 101(4):731-736.
[37]Boger RH, Bode Boger SM. Asymmetric dimethylarginine ,derangements of the endothelial nitric oxide synthase pathway, and cardiovascular diseases. Sem Thromb Hemost. 2000; 26: 539-545.
[38]Vallance P, Leone A, Calver A, Collier J, Moncada S. Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure. Lancet. 1992; 339(8793):572-575.
[39]Leiper JM, Santa Maria J, Chubb A, et al. Identification of two human dimethylarginine dimethylaminohydrolases with distinct tissue distributions and hology with microbial arginine deiminases. Biochem J. 1999; 343: 209-214.
[40]Dayoub H, Achan V, Adimoolam S, et al. Dimethylarginine dimethylaminohydrolase regulates nitric oxide synthesis: genetic and physiological evidence. Circulation. 2003;108(24): 3042-3047.
[41]Schmieder RE. Endothelial dysfunction: how can one intervene at the beginning of the cardiovascular continuum. J Hypertens. 2006; 24: S31-S35.
[42]Takai S, Kirimura K, Jin D, et ah Significance of angiotensin Ⅱ receptor blocker lipo- philicities lipophilicities and their protective effect against vascular remodeling. Hypertens Res. 2005; 28: 593-600.
[43]Kajihara N, Nishida T, Boku N, et ah Angiotensin Ⅱtype 1 receptor antagonist protects ventricular and coronary endothelial function after 24-hour heart preservation. J Heart Lung Transplant. 2005; 24: 2211-2217.
[44] Benson SC, Pershadsingh HA, Ho CI, et al. Identification of telmisartan as a unique angiotensin Ⅱ receptor antagonist with selective PPARy modulating activity. Hypertension. 2004; 43: 993-1002.
[45]Scalera F, Martens LJ, Alicja B, et ah Effect of Telmisartan on Nitric Oxide- Asymmetrical Dimethylarginine System Role of Angiotensin Ⅱ Type 1 Receptor and Peroxisome Proliferator Activated Receptor-y Signaling During Endothelial Aging. Hypertension. 2008; 51: 696-703.
[46]Voelter-Mahlknecht S, Mahlknecht U. Cloning, chromosomal characterization and mapping of the NAD-dependent histone deacetylases gene sirtuin 1. Int J Mol Med. 2006; 17(1): 59-67.
[47]Boger RH. The emerging role of asymmetric dimethylarginine as a novel cardiovascular risk factor. Cardiovasc Res. 2003; 59: 824-833.
[48]Unceta N, San Vicente A, Goicolea MA, et ah Determination of methylarginines in human plasma by HPLC with precolumn derivatization using naphthalenedicarbo- xaldehyde as fluorogenic agent. J Sep Sci. 2002; 25: 665-670.
[49]Holven KB, Haugstad TS, Holm T, et ah Folic acid treatment reduces elevated plasma levels of asymmetric dimethylarginine in hyperhomocysteinaemic subjects. Br J Nutr 2003; 89: 359-363.
[50]Marra M, Bonfigli AR, Testa R, et ah High-performance liquid chromatographic assay of asymmetric dimethylarginine, symmetric dimethylarginine, and arginine in human plasma by derivatization with naphthalene-2,3-dicarboxaldehyde. Anal Biochem. 2003;318: 13-17.
[51]Teerlink T, Nijveldt RJ, de Jong S, et ah Determination of arginine, asymmetric dimethylarginine, and symmetric dimethylarginine in human plasma and other biological samples by high-performance liquid chromatography. Anal Biochem. 2002;303: 131-137.
[52]Heresztyn T, Worthley MI, Horowitz JD. Determination of Larginine and NG, NG -dimethyl-L-arginine in plasma by liquid chromatography as AccQ-FluorTM fluorescent derivatives. J Chromatogr B Biomed Sci Appl. 2004; 805: 325-329.
[53]Petterson A, Uggla L, Backman V. Determination of dimethylated arginines in human plasma by high-performance liquid chromatography. J Chromatogr B Biomed Sci Appl.1997; 692: 257-262.
[54] Pi J, Kumagai Y, Sun G, et al. Improved method for simultaneous determination of L-arginine and its mono- and dimethylated metabolites in biological samples by high-performance liquid chromatography. J Chromatogr B Biomed Sci Appl. 2000;742: 199-203.
[55]Ono Y, Nakaya Y, Bando S, et al. Telmisartan decreases plasma levels of asymmetrical dimethyl-L-arginine and improves lipid and glucose metabolism and vascular function.Int Heart J. 2009; 50(1): 73-83.
[1] Gerloff, T. Impact of genetic polymorphisms in transmembrane carriersystems on drug and xenobiotic distribution. Naunyn-Schmiedeberg's. Arch Pharmacol. 2004; 369: 69-77.
[2] Juranka PF, Zastawny RL, Ling V. P-glycoprotein: multidrugresistance and a superfamily of membrane-associated transport proteins. FASEB J. 1989. 3: 2583-2592.
[3] Schinkel AH, Jonker JW. Mammalian drug efflux transporters of the ATP binding cassette (ABC) family: an overview[J]. Adv Drug Deliv Rev, 2003, 55(1): 3229.
[4] Efferth T. The human ATP-binding cassette transporter genes: from the bench to the bedside. Curr Mol Med 2001; 1:45-65.
[5] Ambudkar SV, Kimchi-Sarfaty C, Sauna ZE, et al. P-glycoprotein: from genomics to mechanism. Oncogene 2003; 22: 7468-7485.
[6] Almond LM, Edirisinghe D, Dalton M, et al. Intracellular and plasma pharmacokinetics of nevirapine in human immunodeficiency virus-infected individuals. Clin Pharmacol Ther 2005; 78:132-142.
[7] Eap CB, Fellay J , Buclin T, et al. CYP3A activity measured by the midazolam test is not related to 3435 C > T polymorphism in the multiple drug resistance transporter gene. Pharmacogenetics,2004, 14: 255-260.
[8] Schinkel AH, Wagenaar E, Mol CA, et al. P-glycoprotein in the blood-brain barrier of mice influences the brain penetration and pharmacological activity of many drugs. J Clin Invest. 1996, 97:2517-2524.
[9] Terao T, Hisanaga E, Sai Y, et al. Active secretion of drugs from the small intestinal epithelium in rats by Pglycoprotein functioning as an absorption barrier. J Pharm Pharmacol. 1996, 48:1083-1089.
[10] Zhang Y, Benet LZ. The gut as a barrier to drug absorption: combined role of cytochrome P450 3A and P-glycoprotein. Clin Pharmacokinet. 2001, 40: 159-168.
[11] von Richter O, Burk O, Fromm MF, et al. Cytochrome P450 3A4 and P-glycoprotein expression in human small intestinal enterocytes and hepatocytes: a comparative analysis in paired tissue specimens. Clin Pharmacol Ther. 2004, 75: 172-183.
[12] Fromm MF. P-glycoprotein: a defense mechanism limiting oral bioavailability and CNS accumulation of drugs. Int J Clin Pharmacol Ther. 2000, 38: 69-74.
[13] Schinkel AH, Mayer U, Wagenaar E, et al. Normal viability and altered pharmacokinetics in mice lacking mdrl-type (drug-transporting) P-glycoproteins. Proc Natl Acad Sci USA. 1997, 94:4028-4033.
[14] Chaudhary PM, Roninson IB. Expression and activity of P-glycoprotein, a multidrug efflux pump, in human hematopoietic stem cells. Cell. 1991, 66: 85-94.
[15] Chaudhary PM, Mechetner EB, Roninson IB. Expression and activity of the multidrug resistance P-glycoprotein in human peripheral blood lymphocytes. Blood. 1992, 80: 2735-2739.
[16] Randolph GJ. Dendritic cell migration to lymph nodes: cytokines, chemokines, and lipid mediators. Semin Immunol. 2001, 13: 267-274.
[17] Schuetz EG, Furuya KN, Schuetz JD. Interindividual variation in expression of P-glycoprotein in normal human liver and secondary hepatic neoplasms. J Pharmacol Exp Ther 1995275, 1011-1018.
[18] Kullak-Ublick GA, Becker MB. Regulation of drug and bile salt transporters in liver and intestine. Drug Metab Rev. 2003, 35: 305-317.
[19] Greiner B, Eichelbaum M, Fritz P, et al. The role of intestinal P-glycoprotein in the interaction of digoxin andrifampin. J Clin Invest. 1999, 104: 147-153.
[20] Giessmann T, May K, Modess C, et al. Carbamazepine regulates intestinal P-glycoprotein and multidrug resistance protein MRP2 and influences disposition of talinolol in humans. Clin Pharmacol Ther. 2004a, 76: 192-200.
[21] Johne A, Brockmoller J, Bauer S. et al. Pharmacokinetic interaction of digoxin with an herbal extract from St. John's wort (Hypericum perforatum). Clin Pharmacol Ther. 1999, 66: 338-345.
[22] Mannel M. Drug interactions with St. John's wort: mechanisms and clinical implications. Drug Saf. 2004,27: 773-797.
[23] Watkins RE, Maglich JM, Moore LB, et al. A crystal structure of human PXR in complex with the St. John's wort compound hyperforin. Biochemistry, 2003, 42: 1430-1438.
[24] Pauli-Magnus C, von Richter O, Burk O, et al. Characterization of the major metabolites of verapamil as substrates and inhibitors of P-glycoprotein. J Pharmacol Exp Ther. 2000, 293:376-382.
[25] Kim RB, Leake BF, Choo EF, et al. Identification of functionally variant MDR1 alleles among European Americans and African Americans. Clin Pharmacol Ther. 2001, 70: 189-199.
[26] Tanabe M, Ieiri I, Nagata N, et al. Expression of P-glycoprotein in human placenta: relation to genetic polymorphism of the multidrug resistance (MDR)-l gene. J Pharmacol Exp Ther. 2001, 297:1137-1143.
[27] Ameyaw MM, Regateiro F. Li T, et al. MDR1 pharmacogenetics: frequency of the C3435T mutation in exon 26 is significantly influenced by ethnicity. Pharmacogenetics. 2001, 11:217-221.
[28] Cascorbi I, Gerloff T, Johne A, et al. Frequency of single nucleotide polymorphisms in the P-glycoprotein drug transporter MDR1 gene in white subjects. Clin Pharmacol Ther. 2001, 69:169-174.
[29] Hoffmeyer S, Burk O, von Richter O, et al. Functional polymorphisms of the human multidrugresistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc Natl Acad Sci USA. 2000, 97: 3473-3478.
[30] Moriya Y, Nakamura T, Horinouchi M, et al. Effects of polymorphisms of MDR1, MRP1, and MRP2 genes on their mRNA expression levels in duodenal enterocytes of healthy Japanese subjects. Biol Pharm Bull. 2002, 25: 1356-1359.
[31] Siegmund W, Altmannsberger S, Paneitz A, et al. Effect of levothyroxine administration on intestinal P-glycoprotein expression: consequences for drug disposition. Clin Pharmacol Ther.2002a, 72: 256-264.
[32] Siegmund W, Ludwig K, Giessmann T, et al. The effects of the human MDR1 genotype on the expression of duodenal P-glycoprotein and disposition of the probe drug talinolol. Clin Pharmacol Ther. 2002b, 72: 572-583.
[33] Fellay J, Marzolini C, Meaden ER, et al. Response to antiretroviral treatment in HIV-1-infected individuals with allelic variants of the multidrug resistance transporter 1: a pharmacogenetics study. Lancet. 2002, 359: 30-36.
[34] Oselin K, Gerloff T, Mrozikiewicz PM, et al. MDR1 polymorphisms G2677T in exon 21 and C3435T in exon 26 fail to affect rhodamine 123 efflux in peripheral blood lymphocytes. Fundam Clin Pharmacol. 2003a, 17:463-469.
[35] Oselin K, Mrozikiewicz PM, Gaikovitch E, et al. Frequency of MRP 1 genetic polymorphisms and their functional significance in Caucasians: detection of a novel mutation G816A in the human MRP1 gene. Eur J Clin Pharmacol. 2003b, 59: 347-350.
[36] Hitzl M, Schaeffeler E, Hocher B, et al. Variable expression of P-glycoprotein in the human placenta and its association with mutations of the multidrug resistance 1 gene (MDR1, ABCB1 ). Pharmacogenetics, 2004, 14: 309-318.
[37] Meissner K, Jedlitschky G, Meyer SH, et al. Modulation of multidrug resistance P-glycoprotein 1 (ABCB1) expression in human heart by hereditary polymorphisms. Pharmacogenetics, 2004, 14:381-385.
[38] Sakaeda T, Nakamura T, Horinouchi M, et al. MDR1 genotype-related pharmacokinetics of digoxin after single oral administration in healthy Japanese subjects. Pharm Res. 2001, 18:1400-1404.
[39] Morita Y, Sakaeda T, Horinouchi M, et al. MDR1 genotype-related duodenal absorption rate of digoxin in healthy Japanese subjects. Pharm Res. 2003, 20: 552-556.
[40] Kurata Y, Ieiri I, Kimura M, et al. Role of human MDR1 gene polymorphism in bioavailability and interaction of digoxin, a substrate of P-glycoprotein. Clin Pharmacol Ther. 2002, 72: 209-219.
[41] Verstuyft C, Schwab M, Schaeffeler E, et al. Digoxin pharmacokinetics and MDR1 genetic polymorphisms. Eur J Clin Pharmacol. 2003, 58: 809-812.
[42] Yi SY, Hong KS, Lim HS, et al. A variant 2677A allele of the MDR1 gene affects fexofenadine disposition. Clin Pharmacol Ther, 2004,76:418-427.
[43] Chowbay B, Cumaraswamy S, Cheung YB, et al. Genetic polymorphisms in MDR1 and CYP3A4 genes in Asians and the influence of MDR1 haplotypes on cyclosporin disposition in heart transplant recipients. Pharmacogenetics. 2003, 13: 89-95.
[44] Anglicheau D, Thervet E, Etienne I, et al. CYP3A5 and MDR1 genetic polymorphisms and cyclosporine pharmacokinetics after renal transplantation. Clin Pharmacol Ther. 2004, 75: 422-433.
[45] Goto M, Masuda S, Saito H, et al. C3435T polymorphism in the MDR1 gene affects the enterocyte expression level of CYP3A4 rather than Pgp in recipients of living-donor liver transplantation. Pharmacogenetics. 2002, 12: 451-457.
[46] Tsuchiya N, Satoh S, Tada H, et al. Influence of CYP3A5 and MDR1 (ABCB1) polymorphisms on the pharmacokinetics of tacrolimus in renal transplant recipients. Transplantation, 2004, 78: 1182-1187.
[47] Haufroid V, Mourad M, Van Kerckhove V, et al. The effect of CYP3A5 andMDRl (ABCB1) polymorphisms on cyclosporine and tacrolimus dose requirements and trough blood levels in stable renal transplant patients. Pharmacogenetics, 2004, 14: 147-154.
[48] Zheng H, Zeevi A, Schuetz E, et al. Tacrolimus dosing in adult lung transplant patients is related to cytochrome P4503A5 gene polymorphism. J Clin Pharmacol. 2004,44: 135-140.
[49] Zhang X, Liu ZH, Zheng JM., et al. Influence of CYP3A5 and MDR1 polymorphisms on tacrolimus concentration in the early stage after renal transplantation. Clin Transplant. 2005, 19: 638-643.
[50] Zhu D, Taguchi-Nakamura H, Goto M, et al. Influence of single-nucleotide polymorphisms in the multidrug resistance-1 gene on the cellular export of nelfinavir and its clinical implication for highly active antiretroviral therapy. Antivir Ther. 2004, 9(6): 929-935.
[51] Zheng H, Webber S, Zeevi A, et al. The MDR1 polymorphisms at exons 21 and 26 predict steroid weaning in pediatric heart transplant patients. Hum Immunol. 2002, 63(9): 765-770.
[52] Siddiqui A, Kerb R., Weale ME, et al. Association of multidrug resistance in epilepsy with a polymorphism in the drug-transporter gene ABCB1. N Engl J Med. 2003, 348: 1442-1448.
[53] Suzuki H, Sugiyama Y Single nucleotide polymorphisms in multidrug resistance associated protein 2 (MRP2/ABCC2): its impact on drug disposition. Adv Drug Deliv Rev. 2002; 54(10): 1311-1331.
[54] Payen L, Sparfel L, Courtois A, et al. The drug efflux pump MRP2: regulation of expression in physiopathological situations and by endogenous and exogenous compounds. Cell Biol. Toxicol. 2002; 18: 221-233.
[55] Elferink R. O., Groen A. K. Genetic defects in hepatobiliary transport. Biochim. Biophys. Acta. 2002; 1586: 129-145.
[56] Borst P., Elferink R. O. Mammalian ABC transporters in health and disease. Annu. Rev. Biochem. 2002; 71: 537-592.
[57] Keitel V., Kartenbeck J., Nies A. T., et al. Impaired protein maturation of the conjugate export pump multidrug resistance protein 2 as a consequence of a deletion mutation in Dubin-Johnson syndrome. Hepatology. 2000; 32: 1317-1328.
[58] Hashimoto K., Uchiumi T., Konno T., et al. Trafficking and functional defects by mutations of the ATP-binding domains in MRP2 in patients with Dubin-Johnson syndrome. Hepatology. 2002; 36:1236-1245.
[59] Nishino A, Kato Y, Igarashi T, et al. Both cMOAT/MRP2 and Another Unknown Transporter(s) Are Responsible for the Biliary Excretion of Glucuronide Conjugate of the Nonpeptide Angiotensin Ⅱ Antagonist, Telmisaltan. Drug Metab Dispos. 2000; 28(10): 1146-1148.
[60] Nies AT, Konig J, Pfannschmidt M, et al. Expression of the multidrug resistance proteins MRP2 and MRP3 in human hepatocellular carcinoma. Int J Cancer. 2001 , 94(4): 492-499.
[61] Ito S., Ieiri I., Tanabe M., et al. Polymorphism of the ABC transporter genes, MDR1, MRP1 and MRP2/cMOAT, in healthy Japanese subjects. Pharmacogenetics. 2001; 11: 175-184.
[62] Itoda M, Saito Y, Soyama A, et al. Polymorphisms in the ABCC2 (cMOAT/MRP2) gene found in 72 established cell lines derived from Japanese individuals: an association between single nucleotide polymorphisms in the 50- untranslated region and exon 28. Drug Metab Dispos. 2002; 30:363-364.
[63] Innocenti F, Undevia SD, Chen PX, et al. Pharmacogenetic analysis of interindividual irinotecan pharmacokinetic variability: Evidence for functional variant of ABCC2. Proc Am Soc Clin Oncol.2004; 22: 2010.
[64] Lang T, Hitzl M, Burk O, et al. Genetic polymorphisms in the multidrug resistance2associated protein 3 (ABCC3, MRP3) gene and relationship to its mRNA and protein expression in human liver. Pharmacogenetics, 2004, 14: 155-164.
[65] Zamber C P, Lamba J K, Yasuda K, et al. Natural allelic variants of breast cancer resistance protein (BCRP) and their relationship to BCRP expression in human intestine. Pharmacogenetics. 2003, 13:19-28.
[66] B(?)ckstr(?)m G, Taipalensuu J, Melhus H, et al. Genetic variation in the ATP-binding cassette transporter gene ABCG2 (BCRP) in a Swedish population. Eur J Pharm Sci. 2003, 18(5): 359-364.
[67] Wang H, Hao B, Zhou K, et al. Linkage disequilibrium and haplotype architecture for two ABC transporter genes (ABCC1 and ABCG2) in Chinese population: implications for pharmacogenomic ssociation studies. Ann Hum Genet, 2004,68: 563-573.
[68] Konig J, Seithel A, Gradhand U, et al. Pharmacogenomics of human OATP transporters. Naunyn-Schmiedeberg's Arch Pharmacol. 2006; 372: 432-443.
[69] Konig J, Cui Y, Nies AT, et al. Localization and genomic organization of a new hepatocellular organic anion transporting polypeptide. J Biol Chem. 2000; 275: 23161-23168.
[70] Kullak-Ublick GA, Ismair MG, Stieger B, et al. Organic anion-transporting polypeptide B (OATP-B) and its functional comparison with three other OATPs of human liver. Gastroenterology. 2001; 120: 525-533.
[71] Vavricka SR, Van Montfoort J, Ha HR, et al. Interactions of rifamycin SV and rifampicin with organic anion uptake systems of human liver. Hepatology. 2002; 36: 164-172.
[72] Hirano M, Maeda K, Shitara Y, et al. Contribution of OATP2 (OATP1B1) and OATP8 (OATP1B3) to the hepatic uptake of pitavastatin in humans. J Pharmacol Exp Ther 2004; 311: 139-146.
[73] Ismair MG, Stieger B, Cattori V, et al. Hepatic uptake of cholecystokinin octapeptide by organic anion-transporting polypeptides OATP4 and OATP8 of rat and human liver. Gastroenterology.2001; 121:1185-1190.
[74] Shimizu M, Fuse K, Okudaira K, et al. Contribution of OATP (organic anion- transporting polypeptide) family transporters to the hepatic uptake of fexofenadine in humans. Drug Metab Dispos. 2005; 33: 1477-1481.
[75] Ishiguro N, Maeda K, Kishimoto W, et al. Predominant contribution of OATP1B3 to the hepatic uptake of telmisartan, an angiotensin II receptor antagonist, in humans. Drug Metab Dispos. 2006;34: 1109-1115.
[76] Letschert K, Keppler D, Konig J. Mutations in the SLCO1B3 gene affecting the substrate specificity of the hepatocellular uptake transporter OATP1B3 (OATP8). Pharmacogenetics. 2004;14:441-452.
[77] Miura M, Satoh S, Inoue K, et al. Influence of SLCO1B1, 1B3, 2B1 and ABCC2 genetic polymorphisms on mycophenolic acid pharmacokinetics in Japanese renal transplant recipients. Eur J Clin Pharmacol. 2007; 63: 1161-1169.
[78] Sakata T, AnzaiN, Shin HJ, et al. Novel single nucleotide polymorphisms of organic cation transporter 1 (SLC22A1) affecting transport functions. Biochem Biophys Res Commun, 2004, 313:789-793.
[2]Efferth T.The human ATP-binding cassette transporter genes:from the bench to the bedside.Curr Mol Med.2001;1:45-65.
[3]Ambudkar SV,Kimchi-Sarfaty C,Sauna ZE,et al.P-glycoprotein:from genomics to mechanism.Oncogene.2003;22:7468-7485.
[4]Almond LM,Edirisinghe D,Dalton M,et al.Intracellular and plasma pharmacokinetics of nevirapine in human immunodeficiency virus-infected individuals.Clin Pharmacol Ther.2005;78:132-142.
[5]Chang C,Bahadduri PM,Polli JE,et al.Rapid identification of P-glycoprotein substrates and inhibitors.Drug Metab Dispos.2006;34(12):1976-1984.
[6]沈杰,焦正,李中东,等.替米沙坦在Caco-2细胞模型中的体外转运研究[J].中国药学杂志.2006,41(21):1624-1627.
[7]Stangier J,Su CA,Hendriksm G,et al.The effect of TMS on the steady-state pharmacokinetics of digoxin in healthy male volunteers.J Clin Pharmacol.2000;40(12):1373-1379.
[8]Kim RB,Leake BF,Choo EF,et al.Identification of functionally variant MDR1 alleles among European Americans and African Americans.Clin Pharmacol Ther.2001;70:189-199.
[9]Hoffmeyer S,Burk O,von Richter O,et al.Functional polymorphisms of the human multidrug resistance gene:Multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo.Proc Natl Acad Sci.2000;97:3473-3478.
[10]Wang D,Sad(?)e W.Searching for polymorphisms that affect gene expression and mRNA processing:example ABCB1(MDR1).AAPS J.2006;8(3):E515-520.
[11]Aarnoudse AJ,Dieleman JP,Visser LE,et al.Common ATP-binding cassette B1variants are associated with increased digoxin serum concentration.Pharmacogenet Genomics.2008;18(4):299-305.
[12]Suzuki H,Sugiyama Y.Single nucleotide polymorphisms in multidrug resistance associated protein 2(MRP2/ABCC2):its impact on drug disposition.Adv Drug Deliv Rev.2002;54(10):1311-1331.
[13]Payen L,Sparfel L,Courtois A,et al.The drug efflux pump MRP2:regulation of expression in physiopathological situations and by endogenous and exogenous compounds. Cell Biol. Toxicol. 2002; 18: 221-233.
[14]Elferink RO, Groen AK. Genetic defects in hepatobiliary transport. Biochim. Biophys. Acta. 2002; 1586: 129-145.
[15]Borst P, Elferink RO. Mammalian ABC transporters in health and disease. Annu. Rev. Biochem. 2002; 71: 537-592.
[16]Keitel V, Kartenbeck J, Nies AT, et al. Impaired protein maturation of the conjugate export pump multidrug resistance protein 2 as a consequence of a deletion mutation in Dubin-Johnson syndrome. Hepatology. 2000; 32: 1317-1328.
[17] Hashimoto K, Uchiumi T, Konno T, et al. Trafficking and functional defects by utations of the ATP-binding domains in MRP2 in patients with Dubin-Johnson syndrome. Hepatology. 2002; 36: 1236-1245.
[18]Nishino A, Kato Y, Igarashi T, et al. Both cMOAT/MRP2 and Another Unknown Transporter(s) Are Responsible for the Biliary Excretion of Glucuronide Conjugate of the Nonpeptide Angiotensin II Antagonist, Telmisaltan. Drug Metab Dispos. 2000; 28(10): 1146-1148.
[19]Ito S, Ieiri I, Tanabe M, et al. Polymorphism of the ABC transporter genes, MDR1, MRP1 and MRP2/cMOAT, in healthy Japanese subjects. Pharmacogenetics. 2001; 11: 175-184.
[20]Itoda M, Saito Y, Soyama A, et al. Polymorphisms in the ABCC2 (cMOAT/MRP2) gene found in 72 established cell lines derived from Japanese individuals: an association between single nucleotide polymorphisms in the 50- untranslated region and exon 28. Drug Metab Dispos. 2002; 30: 363-364.
[21 ] Innocenti F, Undevia SD, Chen PX, et al. Pharmacogenetic analysis of interindividual irinotecan pharmacokinetic variability: Evidence for functional variant of ABCC2.Proc Am Soc Clin Oncol. 2004; 22: 2010.
[22]Konig J, Seithel A, Gradhand U, et al. Pharmacogenomics of human OATP transporters. Naunyn-Schmiedeberg's Arch Pharmacol. 2006; 372: 432-443.
[23]Konig J, Cui Y, Nies AT, et al. Localization and genomic organization of a new hepatocellular organic anion transporting polypeptide. J Biol Chem. 2000; 275: 23161-23168.
[24] Kullak-Ublick GA, Ismair MG, Stieger B, et al. Organic anion-transporting polypeptide B (OATP-B) and its functional comparison with three other OATPs of human liver. Gastroenterology. 2001; 120: 525-533.
[25]Vavricka SR, Van Montfoort J, Ha HR, et al. Interactions of rifamycin SV and rifampicin with organic anion uptake systems of human liver. Hepatology. 2002; 36:164-172.
[26]Hirano M, Maeda K, Shitara Y, et al. Contribution of OATP2 (OATP1B1) and OATP8 (OATP1B3) to the hepatic uptake of pitavastatin in humans. J Pharmacol Exp Ther 2004; 311: 139-146.
[27]Ismair MG, Stieger B, Cattori V, et al. Hepatic uptake of cholecystokinin octapeptide by organic anion-transporting polypeptides OATP4 and OATP8 of rat and human liver.Gastroenterology. 2001; 121: 1185-1190.
[28]Shimizu M, Fuse K, Okudaira K, et al. Contribution of OATP (organic anion- transporting polypeptide) family transporters to the hepatic uptake of fexofenadine in humans. Drug Metab Dispos. 2005; 33: 1477-1481.
[29]Ishiguro N, Maeda K, Kishimoto W, et al. Predominant contribution of OATP1B3 to the hepatic uptake of telmisartan, an angiotensin II receptor antagonist, in humans.Drug Metab Dispos. 2006; 34: 1109-1115.
[30]Letschert K, Keppler D, Konig J. Mutations in the SLCO1B3 gene affecting the substrate specificity of the hepatocellular uptake transporter OATP1B3 (OATP8).Pharmacogenetics. 2004; 14: 441-452.
[31]Masatomo M, Shigeru S, Kazuyuki I, et al. Influence of SLCO1B1, 1B3, 2B1 and ABCC2 genetic polymorphisms on mycophenolic acid pharmacokinetics in Japanese renal transplant recipients. Eur J Clin Pharmacol. 2007; 63: 1161-1169.
[32]Wienen W, Entzeroth M, van Meel JCA, et al. A review on telmisartan: a novel. long-acting angiotensin II-receptor antagonist. Cardiovascular drug reviews. 2000, 18:127-156.
[33]Stangier J, Schmid J, Turck D, et al. Absorption, metabolism, and excretion of intravenously and orally administered [14C] telmisartan in healthy volunteers. J Clin Pharmacol. 2000b; 40: 1312-1322.
[34] Stangier J, Su CA, Schondorfer G, et al. Pharmacokinetics and safety of intravenous and oral telmisartan 20 mg and 120 mg in subjects with hepatic impairment compared with healthy volunteers. J Clin Pharmacol. 2000a; 40: 1355-1364.
[35]Ishiguro N, Maeda K, Saito A, et al. Establishment of a set of double transfectants coexpressing organic anion transporting polypeptide 1B3 and hepatic efflux transporters for the characterization of the hepatobiliary transport of telmisartan acylglucuronide. Drug Metab Dispos. 2008; 36(4): 796-805.
[36] Giles TD, Bakris GL, Smith DH, et al. Defining the antihypertensive properties of the angiotensin receptor blocker telmisartan by a practice-based clinical trial. Am J Hypertens. 2003; 16(6): 460-466.
[37]Plavnik FL, Ribeiro AB. A multicenter, open-label study of the efficacy and safety of telmisartan in mild to moderate hypertensive patients. Arq Bras Cardiol. 2002; 79(4):339-350.
[3 8] Zhang P, Zhang Y, Chen X, et al. Pharmacokinetics of telmisartan in healthy Chinese subjects after oral administration of two dosage levels. Arzneimittelforschung. 2006;56(8): 569-573.
[39] Smith DH, Matzek KM, Kempthorne-Rawson J. Dose response and safety of telmisartan in patients with mild to moderate hypertension. J Clin Pharmacol. 2000; 40(12): 1380-1390.
[40]Tatami S, Sarashina A, Yamamura N, et al. Population pharmacokinetics of an angiotensinⅡ receptor antagonist, telmisartan, in healthy volunteers and hypertensive patients. Drug Metab Pharmacokinet. 2003; 18(3): 203-211.
[41]Callen DF, Baker E, Simmers RN, et al. Localization of the human multiple drug resistance gene, MDR1, to 7q21.1. Hum Genet. 1987; 77(2): 142-144.
[42]Chinn LW, Kroetz DL. ABCB1 pharmacogenetics: progress, pitfalls, and promise. Clin Pharmacol Then 2007; 81(2): 265-269.
[43] Li D, Zhand GL, Lou YQ, et al. Genetic polymorphisms in MDR1 and CYP3A5 and MDR1 haplotype in mainland Chinese Han, Uygur and Kazakh ethnic groups. J Clin Pharm Ther. 2007; 32: 89-95.
[44] Vicente J, Sinues B, Fanlo A, et al. Polymorphism C3435T of the MDR1 gene in Central Americans and Spaniards. Mol Biol Rep. 2008; 35(3): 473-478.
[45]Hirouchi M, Suzuki H, Itoda M, et al. Characterization of the Cellular Localization, Expression Level, and Function of SNP Variants of MRP2/ABCC. Pharmaceutical Research. 2004; 21(5): 742-748.
[46]Cascorbi I. Role of pharmacogenetics of ATP-binding cassette transporters in the pharmacokinetics of drugs. Pharmacol Ther. 2006; 112(2): 457-473.
[47]Haenisch S, Mossiaguine I, Siegmund W, et al. Frequency of single nucleotide polymorphisms in the MRP2 gene in healthy German subjects. Eur J Clin Pharmacol.2002; 58: S95.
[48]Iida A, Saito S, Sekine A, et al.Catalog of 258 single-nucleotide polymorphisms (SNPs) in genes encoding three organic anion transporters, three organic anion-transporting polypeptides, and three NADH:ubiquinone oxidoreductase flavoproteins. J Hum Genet. 200l;46(11):668-683.
[49]赵霞,许俊羽,刘文英.反相高效液相色谱法测定大鼠血浆中替米沙坦的浓度.中国药科大学学报.2003;34(3):247-248.
[50]武洁,冯芳,蒋娟娟,等.HPLC-MS法测定人血浆中替米沙坦及药代动力学研究.中国药科大学学报.2004;35(6):545-547.
[51]沈杰,焦正,李中东,等.HPLC荧光法测定人血浆中替米沙坦的浓度.药物分析杂志.2005;25(1):47-49.
[52]Loeuillet C,Weale M,Deutsch S,et al.Promoter polymorphisms and allelic imbalance in ABCB1 expression.Pharmacogenet Genomics.2007;17(11):951-959.
[53]Miura M,Satoh S,Inoue K,et al.Telmisartan pharmacokinetics in Japanese renal transplant recipients.Clin Chim Acta.2009;399(1-2):83-87.
[1]Michel MC,Bohner H,Koster J,et al.Safety of telmisartan in patients with arterial hypertension:an open-label observational study.Drug Saf.2004;27:335-344.
[2]柏瑾,诸骏仁,蔡绳,等.替米沙坦治疗轻中度高血压的临床疗效和安全性.中华心血管病杂志.2002;30:738-742.
[3]于海波,韩雅玲,王祖禄,等.替米沙坦降压疗效的临床研究.高血压杂志.2004;12(6):515-518.
[4]程澜.血管紧张素Ⅱ受体阻断剂替米沙坦改善糖、脂代谢及抗动脉粥样硬化的作用机制及应用进展血管病学进展.2008;29(3):494-496.
[5]Takaya T,Kawashima S,Shinohara M,et al.Angiotensin Ⅱ type 1 receptor blocker telmisartan suppresses superoxide production and reduces atherosclerotic lesion formation in apolipoprotein E-deficient mice.Atherosclerosis.2006;186:402-410.
[6]Giles TD,Bakris GL,Smith DH,et al.Defining the antihypertensive properties of the angiotensin receptor blocker telmisartan by a practice-based clinical trial.Am J Hypertens.2003;16(6):460-466.
[7]Plavnik FL,Ribeiro AB.A multicenter,open-label study of the efficacy and safety of telmisartan in mild to moderate hypertensive patients.Arq Bras Cardiol.2002;79(4):339-350.
[8]Redon J,Luque-Otero M,Martell N,et al.Investigators.Renin-angiotensin system gene polymorphisms:relationship with blood pressure and microalbuminuria in telmisartan-treated hypertensive patients.Pharmacogenomics J.2005;5(1):14-20.
[9]郭韶洁,赵秀丽,武峰,等.内皮型一氧化氮合酶基因G894T多态性与替米沙坦降压效果的相关性.首都医科大学学报.2007;28(1):107-109.
[10]Strahl BD,Allis CD.The language of covalent histone modifications.Nature.2000;403(6765):41-45.
[11]Bitterman KJ,Anderson RM,Cohen HY,et al.Inhibition of silencing and accelerated aging by nicotinamide,a putative negative regulator of yeast sir2 and human SIRT1.J Biol Chem.2002;277(47):45099-45107.
[12]Blander G,Guarente L.The Sir2 family of protein deacetylases(Review).Armu Rev Biochem.2004;73:417-35.
[13]Frye RA.Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins.Biochem Biophys Res Commun.2000;273(2):793-798.
[14]Frye RA.Characterization of five human cDNAs with homology to the yeast SIR2gene:Sir2-like proteins(sirtuins) metabolize NAD and may have protein ADP- ribosyltransferase activity. Biochem Biophys Res Commun. 1999; 260(1): 273-279.
[15]Luo J, Nikolaev AY, Imai S, et al. Negative control of p53 by Sir2alpha promotes cell survival under stress. Cell. 2001; 107(2): 137-148.
[16]Vaziri H, Dessain SK, Ng Eaton E, et al. hSIR2 (SIRT1) functions as an NAD- dependent p53 deacetylase. Cell. 2001; 107 (2): 149-159.
[17]Senawong T, Peterson VJ, Avram D, et al. Involvement of the histone deacetylase SIRT1 in chicken ovalbumin upstream promoter transcription factor (COUP-TF)- interacting protein 2-mediated transcriptional repression. J Biol Chem. 2003; 278(44):43041-43050.
[18]Takata T, Ishikawa FH. Sir2-related protein SIRT1 associates with the bHLH repressors HES1 and HEY2 and is involved in HES1-and HEY2-mediated transcriptional repression. Biochem Biophys Res Commun. 2003; 301(1): 250-257.
[19]Fulco M, Schiltz RL, Iezzi S, et al. Sir2 regulates skeletal muscle differentiation as a potential sensor of the redox state. Molecular Cell. 2003; 12: 51-62.
[20]Brunet A, Sweeney LB, Sturgill JF, et al. Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science. 2004; 303(5666): 2011-2015.
[21]Motta MC, Divecha N, Lemieux M, et al. Mammalian SIRT1 represses forkhead transcription factors. Cell. 2004; 16(4): 551-563.
[22]Picard F, Kurtev M, Chung N, et al. Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-gamma. Nature. 2004; 429(6993): 771-776.
[23] Yeung F, Hoberg JE, Ramsey CS, et al. Modulation of NF-kappaB-dependent transcription and cell survival by the SIRT1 deacetylase. EMBO J. 2004; 23(12): 2369-2380.
[24] Cohen HY, Miller C, Bitterman KJ, et al. Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. Science. 2004; 305(5682): 390-392.
[25]Chua KF, Mostoslavsky R, Lombard DB, et al. Mammalian SIRT1 limits replicative life span in response to chronic genotoxic stress. Cell metabolism. 2005; 2: 67-76.
[26]Kobayashi Y, Furukawa-Hibi Y, Chen C, et al. SIRT1 is critical regulator of FOXO-mediated transcription in response to oxidative stress. Int J Mol Med. 2005;16(2): 237-243.
[27] Zhou B, Wu LJ, Li LH, et al. Silibinin protects against isoproterenol-induced rat cardiac myocyte injury through mitochondrial pathway after up-regulation of SIRT1. J Pharmacol Sci. 2006; 102(4): 387-395.
[28]Alcendor RR, Gao S, Zhai P, et.al. Sirtl regulates aging and resistance to oxidative stress in the heart. Circ Res. 2007; 100(10): 1512-1521.
[29]Alcendor RR, Kirshenbaum LA, Imai S, et al. Silent information regulator 2alpha, a longevity factor and class Ⅲ histone deacetylase, is an essential endogenous apoptosis inhibitor in cardiac myocytes. Circ Res. 2004; 95(10): 971-980.
[30]Regula KM, Kirshenbaum LA. p53 activates the mitochondrial death pathway and apoptosis of ventricular myocytes independent of de novo gene transcription. J Mol Cell Cardiol. 2001; 33(8): 1435-1445.
[31] Miyazaki R, Ichiki T, Hashimoto T, et al. SIRT1, a longevity gene, downregulates angiotensinⅡ type 1 receptor expression in vascular smooth muscle cells. Arterioscler Thromb Vase Biol. 2008; 28(7): 1263-1269.
[32]Peeters AV, Beckers S, Verrijken A, et al. Association of SIRT1 gene variation with visceral obesity. Hum Genet. 2008; 124(4): 431-436.
[33]Helisalmi S, Vepsalainen S, Hiltunen M, et al. Genetic study between SIRT1, PPARD, PGC-1 alpha genes and Alzheimer's disease. J Neurol. 2008; 255(5): 668-73.
[34]Lagouge M, Argmann C, Gerhart-Hines Z, et al. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1 alpha. Cell. 2006; 127(6): 1109-22.
[35]Gokce N. L-arginine and hypertension. J Nutr. 2004; 134(10 Suppl 1): 2807S-2811S.
[36]Rudic RD, Shesely EG, Maeda N, et al. Direct evidence for the importance of endo- thelium-derived nitric oxide in vascular remodeling. J Clin Invest. 1998; 101(4):731-736.
[37]Boger RH, Bode Boger SM. Asymmetric dimethylarginine ,derangements of the endothelial nitric oxide synthase pathway, and cardiovascular diseases. Sem Thromb Hemost. 2000; 26: 539-545.
[38]Vallance P, Leone A, Calver A, Collier J, Moncada S. Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure. Lancet. 1992; 339(8793):572-575.
[39]Leiper JM, Santa Maria J, Chubb A, et al. Identification of two human dimethylarginine dimethylaminohydrolases with distinct tissue distributions and hology with microbial arginine deiminases. Biochem J. 1999; 343: 209-214.
[40]Dayoub H, Achan V, Adimoolam S, et al. Dimethylarginine dimethylaminohydrolase regulates nitric oxide synthesis: genetic and physiological evidence. Circulation. 2003;108(24): 3042-3047.
[41]Schmieder RE. Endothelial dysfunction: how can one intervene at the beginning of the cardiovascular continuum. J Hypertens. 2006; 24: S31-S35.
[42]Takai S, Kirimura K, Jin D, et ah Significance of angiotensin Ⅱ receptor blocker lipo- philicities lipophilicities and their protective effect against vascular remodeling. Hypertens Res. 2005; 28: 593-600.
[43]Kajihara N, Nishida T, Boku N, et ah Angiotensin Ⅱtype 1 receptor antagonist protects ventricular and coronary endothelial function after 24-hour heart preservation. J Heart Lung Transplant. 2005; 24: 2211-2217.
[44] Benson SC, Pershadsingh HA, Ho CI, et al. Identification of telmisartan as a unique angiotensin Ⅱ receptor antagonist with selective PPARy modulating activity. Hypertension. 2004; 43: 993-1002.
[45]Scalera F, Martens LJ, Alicja B, et ah Effect of Telmisartan on Nitric Oxide- Asymmetrical Dimethylarginine System Role of Angiotensin Ⅱ Type 1 Receptor and Peroxisome Proliferator Activated Receptor-y Signaling During Endothelial Aging. Hypertension. 2008; 51: 696-703.
[46]Voelter-Mahlknecht S, Mahlknecht U. Cloning, chromosomal characterization and mapping of the NAD-dependent histone deacetylases gene sirtuin 1. Int J Mol Med. 2006; 17(1): 59-67.
[47]Boger RH. The emerging role of asymmetric dimethylarginine as a novel cardiovascular risk factor. Cardiovasc Res. 2003; 59: 824-833.
[48]Unceta N, San Vicente A, Goicolea MA, et ah Determination of methylarginines in human plasma by HPLC with precolumn derivatization using naphthalenedicarbo- xaldehyde as fluorogenic agent. J Sep Sci. 2002; 25: 665-670.
[49]Holven KB, Haugstad TS, Holm T, et ah Folic acid treatment reduces elevated plasma levels of asymmetric dimethylarginine in hyperhomocysteinaemic subjects. Br J Nutr 2003; 89: 359-363.
[50]Marra M, Bonfigli AR, Testa R, et ah High-performance liquid chromatographic assay of asymmetric dimethylarginine, symmetric dimethylarginine, and arginine in human plasma by derivatization with naphthalene-2,3-dicarboxaldehyde. Anal Biochem. 2003;318: 13-17.
[51]Teerlink T, Nijveldt RJ, de Jong S, et ah Determination of arginine, asymmetric dimethylarginine, and symmetric dimethylarginine in human plasma and other biological samples by high-performance liquid chromatography. Anal Biochem. 2002;303: 131-137.
[52]Heresztyn T, Worthley MI, Horowitz JD. Determination of Larginine and NG, NG -dimethyl-L-arginine in plasma by liquid chromatography as AccQ-FluorTM fluorescent derivatives. J Chromatogr B Biomed Sci Appl. 2004; 805: 325-329.
[53]Petterson A, Uggla L, Backman V. Determination of dimethylated arginines in human plasma by high-performance liquid chromatography. J Chromatogr B Biomed Sci Appl.1997; 692: 257-262.
[54] Pi J, Kumagai Y, Sun G, et al. Improved method for simultaneous determination of L-arginine and its mono- and dimethylated metabolites in biological samples by high-performance liquid chromatography. J Chromatogr B Biomed Sci Appl. 2000;742: 199-203.
[55]Ono Y, Nakaya Y, Bando S, et al. Telmisartan decreases plasma levels of asymmetrical dimethyl-L-arginine and improves lipid and glucose metabolism and vascular function.Int Heart J. 2009; 50(1): 73-83.
[1] Gerloff, T. Impact of genetic polymorphisms in transmembrane carriersystems on drug and xenobiotic distribution. Naunyn-Schmiedeberg's. Arch Pharmacol. 2004; 369: 69-77.
[2] Juranka PF, Zastawny RL, Ling V. P-glycoprotein: multidrugresistance and a superfamily of membrane-associated transport proteins. FASEB J. 1989. 3: 2583-2592.
[3] Schinkel AH, Jonker JW. Mammalian drug efflux transporters of the ATP binding cassette (ABC) family: an overview[J]. Adv Drug Deliv Rev, 2003, 55(1): 3229.
[4] Efferth T. The human ATP-binding cassette transporter genes: from the bench to the bedside. Curr Mol Med 2001; 1:45-65.
[5] Ambudkar SV, Kimchi-Sarfaty C, Sauna ZE, et al. P-glycoprotein: from genomics to mechanism. Oncogene 2003; 22: 7468-7485.
[6] Almond LM, Edirisinghe D, Dalton M, et al. Intracellular and plasma pharmacokinetics of nevirapine in human immunodeficiency virus-infected individuals. Clin Pharmacol Ther 2005; 78:132-142.
[7] Eap CB, Fellay J , Buclin T, et al. CYP3A activity measured by the midazolam test is not related to 3435 C > T polymorphism in the multiple drug resistance transporter gene. Pharmacogenetics,2004, 14: 255-260.
[8] Schinkel AH, Wagenaar E, Mol CA, et al. P-glycoprotein in the blood-brain barrier of mice influences the brain penetration and pharmacological activity of many drugs. J Clin Invest. 1996, 97:2517-2524.
[9] Terao T, Hisanaga E, Sai Y, et al. Active secretion of drugs from the small intestinal epithelium in rats by Pglycoprotein functioning as an absorption barrier. J Pharm Pharmacol. 1996, 48:1083-1089.
[10] Zhang Y, Benet LZ. The gut as a barrier to drug absorption: combined role of cytochrome P450 3A and P-glycoprotein. Clin Pharmacokinet. 2001, 40: 159-168.
[11] von Richter O, Burk O, Fromm MF, et al. Cytochrome P450 3A4 and P-glycoprotein expression in human small intestinal enterocytes and hepatocytes: a comparative analysis in paired tissue specimens. Clin Pharmacol Ther. 2004, 75: 172-183.
[12] Fromm MF. P-glycoprotein: a defense mechanism limiting oral bioavailability and CNS accumulation of drugs. Int J Clin Pharmacol Ther. 2000, 38: 69-74.
[13] Schinkel AH, Mayer U, Wagenaar E, et al. Normal viability and altered pharmacokinetics in mice lacking mdrl-type (drug-transporting) P-glycoproteins. Proc Natl Acad Sci USA. 1997, 94:4028-4033.
[14] Chaudhary PM, Roninson IB. Expression and activity of P-glycoprotein, a multidrug efflux pump, in human hematopoietic stem cells. Cell. 1991, 66: 85-94.
[15] Chaudhary PM, Mechetner EB, Roninson IB. Expression and activity of the multidrug resistance P-glycoprotein in human peripheral blood lymphocytes. Blood. 1992, 80: 2735-2739.
[16] Randolph GJ. Dendritic cell migration to lymph nodes: cytokines, chemokines, and lipid mediators. Semin Immunol. 2001, 13: 267-274.
[17] Schuetz EG, Furuya KN, Schuetz JD. Interindividual variation in expression of P-glycoprotein in normal human liver and secondary hepatic neoplasms. J Pharmacol Exp Ther 1995275, 1011-1018.
[18] Kullak-Ublick GA, Becker MB. Regulation of drug and bile salt transporters in liver and intestine. Drug Metab Rev. 2003, 35: 305-317.
[19] Greiner B, Eichelbaum M, Fritz P, et al. The role of intestinal P-glycoprotein in the interaction of digoxin andrifampin. J Clin Invest. 1999, 104: 147-153.
[20] Giessmann T, May K, Modess C, et al. Carbamazepine regulates intestinal P-glycoprotein and multidrug resistance protein MRP2 and influences disposition of talinolol in humans. Clin Pharmacol Ther. 2004a, 76: 192-200.
[21] Johne A, Brockmoller J, Bauer S. et al. Pharmacokinetic interaction of digoxin with an herbal extract from St. John's wort (Hypericum perforatum). Clin Pharmacol Ther. 1999, 66: 338-345.
[22] Mannel M. Drug interactions with St. John's wort: mechanisms and clinical implications. Drug Saf. 2004,27: 773-797.
[23] Watkins RE, Maglich JM, Moore LB, et al. A crystal structure of human PXR in complex with the St. John's wort compound hyperforin. Biochemistry, 2003, 42: 1430-1438.
[24] Pauli-Magnus C, von Richter O, Burk O, et al. Characterization of the major metabolites of verapamil as substrates and inhibitors of P-glycoprotein. J Pharmacol Exp Ther. 2000, 293:376-382.
[25] Kim RB, Leake BF, Choo EF, et al. Identification of functionally variant MDR1 alleles among European Americans and African Americans. Clin Pharmacol Ther. 2001, 70: 189-199.
[26] Tanabe M, Ieiri I, Nagata N, et al. Expression of P-glycoprotein in human placenta: relation to genetic polymorphism of the multidrug resistance (MDR)-l gene. J Pharmacol Exp Ther. 2001, 297:1137-1143.
[27] Ameyaw MM, Regateiro F. Li T, et al. MDR1 pharmacogenetics: frequency of the C3435T mutation in exon 26 is significantly influenced by ethnicity. Pharmacogenetics. 2001, 11:217-221.
[28] Cascorbi I, Gerloff T, Johne A, et al. Frequency of single nucleotide polymorphisms in the P-glycoprotein drug transporter MDR1 gene in white subjects. Clin Pharmacol Ther. 2001, 69:169-174.
[29] Hoffmeyer S, Burk O, von Richter O, et al. Functional polymorphisms of the human multidrugresistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc Natl Acad Sci USA. 2000, 97: 3473-3478.
[30] Moriya Y, Nakamura T, Horinouchi M, et al. Effects of polymorphisms of MDR1, MRP1, and MRP2 genes on their mRNA expression levels in duodenal enterocytes of healthy Japanese subjects. Biol Pharm Bull. 2002, 25: 1356-1359.
[31] Siegmund W, Altmannsberger S, Paneitz A, et al. Effect of levothyroxine administration on intestinal P-glycoprotein expression: consequences for drug disposition. Clin Pharmacol Ther.2002a, 72: 256-264.
[32] Siegmund W, Ludwig K, Giessmann T, et al. The effects of the human MDR1 genotype on the expression of duodenal P-glycoprotein and disposition of the probe drug talinolol. Clin Pharmacol Ther. 2002b, 72: 572-583.
[33] Fellay J, Marzolini C, Meaden ER, et al. Response to antiretroviral treatment in HIV-1-infected individuals with allelic variants of the multidrug resistance transporter 1: a pharmacogenetics study. Lancet. 2002, 359: 30-36.
[34] Oselin K, Gerloff T, Mrozikiewicz PM, et al. MDR1 polymorphisms G2677T in exon 21 and C3435T in exon 26 fail to affect rhodamine 123 efflux in peripheral blood lymphocytes. Fundam Clin Pharmacol. 2003a, 17:463-469.
[35] Oselin K, Mrozikiewicz PM, Gaikovitch E, et al. Frequency of MRP 1 genetic polymorphisms and their functional significance in Caucasians: detection of a novel mutation G816A in the human MRP1 gene. Eur J Clin Pharmacol. 2003b, 59: 347-350.
[36] Hitzl M, Schaeffeler E, Hocher B, et al. Variable expression of P-glycoprotein in the human placenta and its association with mutations of the multidrug resistance 1 gene (MDR1, ABCB1 ). Pharmacogenetics, 2004, 14: 309-318.
[37] Meissner K, Jedlitschky G, Meyer SH, et al. Modulation of multidrug resistance P-glycoprotein 1 (ABCB1) expression in human heart by hereditary polymorphisms. Pharmacogenetics, 2004, 14:381-385.
[38] Sakaeda T, Nakamura T, Horinouchi M, et al. MDR1 genotype-related pharmacokinetics of digoxin after single oral administration in healthy Japanese subjects. Pharm Res. 2001, 18:1400-1404.
[39] Morita Y, Sakaeda T, Horinouchi M, et al. MDR1 genotype-related duodenal absorption rate of digoxin in healthy Japanese subjects. Pharm Res. 2003, 20: 552-556.
[40] Kurata Y, Ieiri I, Kimura M, et al. Role of human MDR1 gene polymorphism in bioavailability and interaction of digoxin, a substrate of P-glycoprotein. Clin Pharmacol Ther. 2002, 72: 209-219.
[41] Verstuyft C, Schwab M, Schaeffeler E, et al. Digoxin pharmacokinetics and MDR1 genetic polymorphisms. Eur J Clin Pharmacol. 2003, 58: 809-812.
[42] Yi SY, Hong KS, Lim HS, et al. A variant 2677A allele of the MDR1 gene affects fexofenadine disposition. Clin Pharmacol Ther, 2004,76:418-427.
[43] Chowbay B, Cumaraswamy S, Cheung YB, et al. Genetic polymorphisms in MDR1 and CYP3A4 genes in Asians and the influence of MDR1 haplotypes on cyclosporin disposition in heart transplant recipients. Pharmacogenetics. 2003, 13: 89-95.
[44] Anglicheau D, Thervet E, Etienne I, et al. CYP3A5 and MDR1 genetic polymorphisms and cyclosporine pharmacokinetics after renal transplantation. Clin Pharmacol Ther. 2004, 75: 422-433.
[45] Goto M, Masuda S, Saito H, et al. C3435T polymorphism in the MDR1 gene affects the enterocyte expression level of CYP3A4 rather than Pgp in recipients of living-donor liver transplantation. Pharmacogenetics. 2002, 12: 451-457.
[46] Tsuchiya N, Satoh S, Tada H, et al. Influence of CYP3A5 and MDR1 (ABCB1) polymorphisms on the pharmacokinetics of tacrolimus in renal transplant recipients. Transplantation, 2004, 78: 1182-1187.
[47] Haufroid V, Mourad M, Van Kerckhove V, et al. The effect of CYP3A5 andMDRl (ABCB1) polymorphisms on cyclosporine and tacrolimus dose requirements and trough blood levels in stable renal transplant patients. Pharmacogenetics, 2004, 14: 147-154.
[48] Zheng H, Zeevi A, Schuetz E, et al. Tacrolimus dosing in adult lung transplant patients is related to cytochrome P4503A5 gene polymorphism. J Clin Pharmacol. 2004,44: 135-140.
[49] Zhang X, Liu ZH, Zheng JM., et al. Influence of CYP3A5 and MDR1 polymorphisms on tacrolimus concentration in the early stage after renal transplantation. Clin Transplant. 2005, 19: 638-643.
[50] Zhu D, Taguchi-Nakamura H, Goto M, et al. Influence of single-nucleotide polymorphisms in the multidrug resistance-1 gene on the cellular export of nelfinavir and its clinical implication for highly active antiretroviral therapy. Antivir Ther. 2004, 9(6): 929-935.
[51] Zheng H, Webber S, Zeevi A, et al. The MDR1 polymorphisms at exons 21 and 26 predict steroid weaning in pediatric heart transplant patients. Hum Immunol. 2002, 63(9): 765-770.
[52] Siddiqui A, Kerb R., Weale ME, et al. Association of multidrug resistance in epilepsy with a polymorphism in the drug-transporter gene ABCB1. N Engl J Med. 2003, 348: 1442-1448.
[53] Suzuki H, Sugiyama Y Single nucleotide polymorphisms in multidrug resistance associated protein 2 (MRP2/ABCC2): its impact on drug disposition. Adv Drug Deliv Rev. 2002; 54(10): 1311-1331.
[54] Payen L, Sparfel L, Courtois A, et al. The drug efflux pump MRP2: regulation of expression in physiopathological situations and by endogenous and exogenous compounds. Cell Biol. Toxicol. 2002; 18: 221-233.
[55] Elferink R. O., Groen A. K. Genetic defects in hepatobiliary transport. Biochim. Biophys. Acta. 2002; 1586: 129-145.
[56] Borst P., Elferink R. O. Mammalian ABC transporters in health and disease. Annu. Rev. Biochem. 2002; 71: 537-592.
[57] Keitel V., Kartenbeck J., Nies A. T., et al. Impaired protein maturation of the conjugate export pump multidrug resistance protein 2 as a consequence of a deletion mutation in Dubin-Johnson syndrome. Hepatology. 2000; 32: 1317-1328.
[58] Hashimoto K., Uchiumi T., Konno T., et al. Trafficking and functional defects by mutations of the ATP-binding domains in MRP2 in patients with Dubin-Johnson syndrome. Hepatology. 2002; 36:1236-1245.
[59] Nishino A, Kato Y, Igarashi T, et al. Both cMOAT/MRP2 and Another Unknown Transporter(s) Are Responsible for the Biliary Excretion of Glucuronide Conjugate of the Nonpeptide Angiotensin Ⅱ Antagonist, Telmisaltan. Drug Metab Dispos. 2000; 28(10): 1146-1148.
[60] Nies AT, Konig J, Pfannschmidt M, et al. Expression of the multidrug resistance proteins MRP2 and MRP3 in human hepatocellular carcinoma. Int J Cancer. 2001 , 94(4): 492-499.
[61] Ito S., Ieiri I., Tanabe M., et al. Polymorphism of the ABC transporter genes, MDR1, MRP1 and MRP2/cMOAT, in healthy Japanese subjects. Pharmacogenetics. 2001; 11: 175-184.
[62] Itoda M, Saito Y, Soyama A, et al. Polymorphisms in the ABCC2 (cMOAT/MRP2) gene found in 72 established cell lines derived from Japanese individuals: an association between single nucleotide polymorphisms in the 50- untranslated region and exon 28. Drug Metab Dispos. 2002; 30:363-364.
[63] Innocenti F, Undevia SD, Chen PX, et al. Pharmacogenetic analysis of interindividual irinotecan pharmacokinetic variability: Evidence for functional variant of ABCC2. Proc Am Soc Clin Oncol.2004; 22: 2010.
[64] Lang T, Hitzl M, Burk O, et al. Genetic polymorphisms in the multidrug resistance2associated protein 3 (ABCC3, MRP3) gene and relationship to its mRNA and protein expression in human liver. Pharmacogenetics, 2004, 14: 155-164.
[65] Zamber C P, Lamba J K, Yasuda K, et al. Natural allelic variants of breast cancer resistance protein (BCRP) and their relationship to BCRP expression in human intestine. Pharmacogenetics. 2003, 13:19-28.
[66] B(?)ckstr(?)m G, Taipalensuu J, Melhus H, et al. Genetic variation in the ATP-binding cassette transporter gene ABCG2 (BCRP) in a Swedish population. Eur J Pharm Sci. 2003, 18(5): 359-364.
[67] Wang H, Hao B, Zhou K, et al. Linkage disequilibrium and haplotype architecture for two ABC transporter genes (ABCC1 and ABCG2) in Chinese population: implications for pharmacogenomic ssociation studies. Ann Hum Genet, 2004,68: 563-573.
[68] Konig J, Seithel A, Gradhand U, et al. Pharmacogenomics of human OATP transporters. Naunyn-Schmiedeberg's Arch Pharmacol. 2006; 372: 432-443.
[69] Konig J, Cui Y, Nies AT, et al. Localization and genomic organization of a new hepatocellular organic anion transporting polypeptide. J Biol Chem. 2000; 275: 23161-23168.
[70] Kullak-Ublick GA, Ismair MG, Stieger B, et al. Organic anion-transporting polypeptide B (OATP-B) and its functional comparison with three other OATPs of human liver. Gastroenterology. 2001; 120: 525-533.
[71] Vavricka SR, Van Montfoort J, Ha HR, et al. Interactions of rifamycin SV and rifampicin with organic anion uptake systems of human liver. Hepatology. 2002; 36: 164-172.
[72] Hirano M, Maeda K, Shitara Y, et al. Contribution of OATP2 (OATP1B1) and OATP8 (OATP1B3) to the hepatic uptake of pitavastatin in humans. J Pharmacol Exp Ther 2004; 311: 139-146.
[73] Ismair MG, Stieger B, Cattori V, et al. Hepatic uptake of cholecystokinin octapeptide by organic anion-transporting polypeptides OATP4 and OATP8 of rat and human liver. Gastroenterology.2001; 121:1185-1190.
[74] Shimizu M, Fuse K, Okudaira K, et al. Contribution of OATP (organic anion- transporting polypeptide) family transporters to the hepatic uptake of fexofenadine in humans. Drug Metab Dispos. 2005; 33: 1477-1481.
[75] Ishiguro N, Maeda K, Kishimoto W, et al. Predominant contribution of OATP1B3 to the hepatic uptake of telmisartan, an angiotensin II receptor antagonist, in humans. Drug Metab Dispos. 2006;34: 1109-1115.
[76] Letschert K, Keppler D, Konig J. Mutations in the SLCO1B3 gene affecting the substrate specificity of the hepatocellular uptake transporter OATP1B3 (OATP8). Pharmacogenetics. 2004;14:441-452.
[77] Miura M, Satoh S, Inoue K, et al. Influence of SLCO1B1, 1B3, 2B1 and ABCC2 genetic polymorphisms on mycophenolic acid pharmacokinetics in Japanese renal transplant recipients. Eur J Clin Pharmacol. 2007; 63: 1161-1169.
[78] Sakata T, AnzaiN, Shin HJ, et al. Novel single nucleotide polymorphisms of organic cation transporter 1 (SLC22A1) affecting transport functions. Biochem Biophys Res Commun, 2004, 313:789-793.