P-gp介导的阿米替林与去甲替林中枢相互作用的体外与体内研究
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摘要
目的：
考察地塞米松与维拉帕米对P-糖蛋白(P-gp)功能及表达影响的时效与量效关系及其对阿米替林与去甲替林外排速率及中枢分布的影响；评估P-gp介导的体外相互作用与脑内相互作用的相关性,探讨利用P-gp介导的相互作用促进药物疗效与减少不良反应的可行性。
方法：
1.采用HaloC18(2.1mm×100mm,2.7μm)色谱柱,纯净水-乙腈(v/v,60：40)为流动相,采用Waters Micromass Quattro PremierXE二极质谱仪为检测器,建立UPLC-MS/MS同时测定阿米替林与去甲替林含量的方法。
2. Caco-2细胞采用MEM培养基进行常规培养,P-糖蛋白表达通过荧光免疫法验证；采用MTT法考察维拉帕米和地塞米松对Caco-2细胞活性的影响；使用流式细胞术考察地塞米松、维拉帕米对罗丹明123摄取的影响。使用免疫荧光与流式细胞术研究地塞米松、维拉帕米对P-糖蛋白表达的影响。
3.将Caco-2细胞接种于transwell板进行培养,构建单层细胞模型,用细胞电位仪、萤光黄及普奈洛尔转运实验对模型进行验证。建模成功后考察地塞米松、维拉帕米对阿米替林与去甲替林的双向跨膜转运的影响。
4.396只昆明种雄性小鼠被随机分成3组,经单次或多次给药后,研究地塞米松与维拉帕米对阿米替林与去甲替林中枢转运的影响。
结果：
1.在实验条件下,地塞米松、维拉帕米及内标物质分离良好,色谱峰尖锐且半峰宽小于0.25s。一次进样的运行时间小于4min。最低检测限为10ng·mL-1。阿米替林与去甲替林在10～2500ng·mL-1浓度范围内线性良好,方法准确、灵敏、简单。
2. Caco-2细胞经复苏后培养成功,荧光免疫法证实了Caco-2细胞中P-糖蛋白强表达。MTT法证实地塞米松、维拉帕米浓度小于100μmol·L-1时,对细胞活性无影响。Rh-123的摄取实验发现在0.01～25μmol·L-1范围内,与空白对照组相比,地塞米松组降低了细胞内荧光强度,降低的幅度为10～60%,荧光强度与浓度呈负相关；而维拉帕米增强了细胞内荧光强度(浓度>0.1μmol-L-1),荧光强度的增加与剂量正相关。免疫荧光实验发现,在1-50μmol·L-1浓度范围内,地塞米松组荧光强度显著强于空白对照组(P<0.05)；维拉帕米组在0.1-50μmol·L-1范围内荧光强度均显著强于空白对照组(P<0.05)。在较低浓度(0.01-0.1μmol·L-1)时,地塞米松对P-gp的表达无影响；维拉帕米浓度为0.01μmol·L-1时,对P-gp表达无影响。
3.显微镜下显示Caco-2单层细胞排列紧密且完整,荧光黄及普萘洛尔跨膜实验证实细胞旁路转运通透性低,而跨细胞转运通路通透性良好。跨膜转运实验证实了阿米替林与去甲替林是P-gp的弱型底物,地塞米松增加了阿米替林和去甲替林的外排速率(增加幅度为10%-60%),而维拉帕米减少了阿米替林和去甲替林的外排速率(减少幅度为10%～20%)。
4.在体动物实验表明地塞米松能减少阿米替林与去甲替林脑组织浓度-时间曲线下面积(AUC)值,减少程度大约为40～50%,而维拉帕米能增加阿米替林与去甲替林AUC值,增加程度大约为10%～50%。
结论：
地塞米松能增强P-糖蛋白的功能,同时诱导其表达,增加了阿米替林与去甲替林的外排速率,减少中枢分布,而维拉帕米能抑制P-糖蛋白功能,诱导其表达,总体表现为抑制了P-gp的外排速率,增加阿米替林与去甲替林的中枢分布。体外与体内研究结果基本一致,说明P-gp介导的中枢相互作用可以通过体外研究实现,利用P-gp介导的相互作用能改变中枢的药动学,达到增强药物疗效,减少药物的不良反应的目的,亦可用于中枢药物过量时的解毒。
Objective
To study the effect of dexamethasone (Dex) and verapamil(Ver) on the function and expression of P-glycoprotein, and their effect on the efflux ratio and the distritribution into brain of amitriptyline (Ami) and nortriptyline(Nor). To investigate the correlation between in vitro and in vivo results of drug interactions. And to assess the feasibility of predicting outcomes of interactions in central nervous system based on the results in vitro and improving the efficacy and decreasing adverse reactions by utilizing P-glycoprotein mediated interactions.
Methods
1. Blood samples were prepared with protein precipitation, and Halo C18column was performed with the mobile phase consisting water and acetonitrile, and samples were detected on a triple-quadrupole tandem mass spectrometer by multiple reaction monitoring (MRM).
2. Caco-2cells were cultured with MEM which contains10%FBS(Fetal Bovine Serum) in a humidified atmosphere of95%air and5%CO2at37℃. The expression of P-glycoprotein in the cells was identified by immunofluorescence assay. Activity of Caco-2cells was assessed by MTT (Methyl thiazolyl tetrazolium) assay. Fluorescence spectrophotometric method and flowcytometry were used to study the effects of Ver and Dex on the efflux of Rhodamine123. The expression of P-glycoprotein in Caco-2cells was measured by immunofluorescence method.
3. The efflux ratios (RE) of Ami and Nor were investigated with Caco-2cells monolayer model in transwell plates.
4.396Kunming male mice were divided into three groups, and the concentration of Ami and Nor in plasma and brain tissues were detected by UPLC-MS/MS after simultaneous intraperitoneal injection Ami or Nor and a single dose or multiple doses of Dex or Ver.
Results
1. UPLC-ESI-MS/MS in the MRM model methodology provides a highly sensitive, selective, reliable and rapid method for determination of Ami and Nor. The linear calibration curves of Ami and Nor were obtained in the concentration10ng mL-1～2500ng mL-1. The extraction recoveries were74.3%-78.6%, intra-and inter-day precision of the assay at three concentrations were2.8%-14.1%with accuracy of95%-105%.
2. Caco-2cells grew very well and the expression of p-glycoprotein was plentiful in Caco-2cells. Dex and Ver did not affect the activity of Caco-2cells when the concentrations were less than100μmol-L-1. Dex can decrease the fluorescence intensity obout20-50%, and there was a significant negative correlation between fluorescence intensity and the dosage when the concentration of Dex was less than25μmol·L-1. Ver can increase the fluorescence intensity in a dose-dependent manner.
The study of expression of P-gp showed that there was no difference between Dex group(within0.01～0.1μmol·L-1) and control group in the fluorescence (P>0.05). When the concentration of Dex was within1～50μmol·L-1, the fluorescence of Dex group was significantly higher than that of control group (P<0.05); When the concentration of Ver was within0.1～50μmol·L-1, the fluorescence of Ver group was significantly higher than that of control group (P<0.05).
3. The study of monolayer model showed that Ami and Nor are the poor substrates of P-glycoprotein and the efflux ratio of Ami and Nor were increased about10to60percents in presence of Dex and decreased about10to20percents in presence of Ver.
4. Dex can decrease the value of AUC of brain tissue in mice about40to50percent and Ver increased the AUC about10to50percents. There were no differences in Cmax between Dex group, Ver group and control group.
Conclusion
Dex can induce the function and the expression of P-gp, and Ver can inhibit the function and induce the expression of P-glycoprotein. Ami and Nor both are the poor substrates of P-gp. The efflux ratio of Ami and Nor can be increased by Dex and decreased by Ver. Results in vivo showed that distribution of Ami and Nor into the brain was increased by Ver and decreased by Dex.
The studies showed that the results in vitro can predict the outcomes of drug-drug interactions in central nervous system. Inducer and inhibitor can modulate the function and expression of P-glycoprotein, which indicates that rational use inducer and inhibitor can improve the curative effect and decrease adverse reactions.
考察地塞米松与维拉帕米对P-糖蛋白(P-gp)功能及表达影响的时效与量效关系及其对阿米替林与去甲替林外排速率及中枢分布的影响；评估P-gp介导的体外相互作用与脑内相互作用的相关性,探讨利用P-gp介导的相互作用促进药物疗效与减少不良反应的可行性。
方法：
1.采用HaloC18(2.1mm×100mm,2.7μm)色谱柱,纯净水-乙腈(v/v,60：40)为流动相,采用Waters Micromass Quattro PremierXE二极质谱仪为检测器,建立UPLC-MS/MS同时测定阿米替林与去甲替林含量的方法。
2. Caco-2细胞采用MEM培养基进行常规培养,P-糖蛋白表达通过荧光免疫法验证；采用MTT法考察维拉帕米和地塞米松对Caco-2细胞活性的影响；使用流式细胞术考察地塞米松、维拉帕米对罗丹明123摄取的影响。使用免疫荧光与流式细胞术研究地塞米松、维拉帕米对P-糖蛋白表达的影响。
3.将Caco-2细胞接种于transwell板进行培养,构建单层细胞模型,用细胞电位仪、萤光黄及普奈洛尔转运实验对模型进行验证。建模成功后考察地塞米松、维拉帕米对阿米替林与去甲替林的双向跨膜转运的影响。
4.396只昆明种雄性小鼠被随机分成3组,经单次或多次给药后,研究地塞米松与维拉帕米对阿米替林与去甲替林中枢转运的影响。
结果：
1.在实验条件下,地塞米松、维拉帕米及内标物质分离良好,色谱峰尖锐且半峰宽小于0.25s。一次进样的运行时间小于4min。最低检测限为10ng·mL-1。阿米替林与去甲替林在10～2500ng·mL-1浓度范围内线性良好,方法准确、灵敏、简单。
2. Caco-2细胞经复苏后培养成功,荧光免疫法证实了Caco-2细胞中P-糖蛋白强表达。MTT法证实地塞米松、维拉帕米浓度小于100μmol·L-1时,对细胞活性无影响。Rh-123的摄取实验发现在0.01～25μmol·L-1范围内,与空白对照组相比,地塞米松组降低了细胞内荧光强度,降低的幅度为10～60%,荧光强度与浓度呈负相关；而维拉帕米增强了细胞内荧光强度(浓度>0.1μmol-L-1),荧光强度的增加与剂量正相关。免疫荧光实验发现,在1-50μmol·L-1浓度范围内,地塞米松组荧光强度显著强于空白对照组(P<0.05)；维拉帕米组在0.1-50μmol·L-1范围内荧光强度均显著强于空白对照组(P<0.05)。在较低浓度(0.01-0.1μmol·L-1)时,地塞米松对P-gp的表达无影响；维拉帕米浓度为0.01μmol·L-1时,对P-gp表达无影响。
3.显微镜下显示Caco-2单层细胞排列紧密且完整,荧光黄及普萘洛尔跨膜实验证实细胞旁路转运通透性低,而跨细胞转运通路通透性良好。跨膜转运实验证实了阿米替林与去甲替林是P-gp的弱型底物,地塞米松增加了阿米替林和去甲替林的外排速率(增加幅度为10%-60%),而维拉帕米减少了阿米替林和去甲替林的外排速率(减少幅度为10%～20%)。
4.在体动物实验表明地塞米松能减少阿米替林与去甲替林脑组织浓度-时间曲线下面积(AUC)值,减少程度大约为40～50%,而维拉帕米能增加阿米替林与去甲替林AUC值,增加程度大约为10%～50%。
结论：
地塞米松能增强P-糖蛋白的功能,同时诱导其表达,增加了阿米替林与去甲替林的外排速率,减少中枢分布,而维拉帕米能抑制P-糖蛋白功能,诱导其表达,总体表现为抑制了P-gp的外排速率,增加阿米替林与去甲替林的中枢分布。体外与体内研究结果基本一致,说明P-gp介导的中枢相互作用可以通过体外研究实现,利用P-gp介导的相互作用能改变中枢的药动学,达到增强药物疗效,减少药物的不良反应的目的,亦可用于中枢药物过量时的解毒。
Objective
To study the effect of dexamethasone (Dex) and verapamil(Ver) on the function and expression of P-glycoprotein, and their effect on the efflux ratio and the distritribution into brain of amitriptyline (Ami) and nortriptyline(Nor). To investigate the correlation between in vitro and in vivo results of drug interactions. And to assess the feasibility of predicting outcomes of interactions in central nervous system based on the results in vitro and improving the efficacy and decreasing adverse reactions by utilizing P-glycoprotein mediated interactions.
Methods
1. Blood samples were prepared with protein precipitation, and Halo C18column was performed with the mobile phase consisting water and acetonitrile, and samples were detected on a triple-quadrupole tandem mass spectrometer by multiple reaction monitoring (MRM).
2. Caco-2cells were cultured with MEM which contains10%FBS(Fetal Bovine Serum) in a humidified atmosphere of95%air and5%CO2at37℃. The expression of P-glycoprotein in the cells was identified by immunofluorescence assay. Activity of Caco-2cells was assessed by MTT (Methyl thiazolyl tetrazolium) assay. Fluorescence spectrophotometric method and flowcytometry were used to study the effects of Ver and Dex on the efflux of Rhodamine123. The expression of P-glycoprotein in Caco-2cells was measured by immunofluorescence method.
3. The efflux ratios (RE) of Ami and Nor were investigated with Caco-2cells monolayer model in transwell plates.
4.396Kunming male mice were divided into three groups, and the concentration of Ami and Nor in plasma and brain tissues were detected by UPLC-MS/MS after simultaneous intraperitoneal injection Ami or Nor and a single dose or multiple doses of Dex or Ver.
Results
1. UPLC-ESI-MS/MS in the MRM model methodology provides a highly sensitive, selective, reliable and rapid method for determination of Ami and Nor. The linear calibration curves of Ami and Nor were obtained in the concentration10ng mL-1～2500ng mL-1. The extraction recoveries were74.3%-78.6%, intra-and inter-day precision of the assay at three concentrations were2.8%-14.1%with accuracy of95%-105%.
2. Caco-2cells grew very well and the expression of p-glycoprotein was plentiful in Caco-2cells. Dex and Ver did not affect the activity of Caco-2cells when the concentrations were less than100μmol-L-1. Dex can decrease the fluorescence intensity obout20-50%, and there was a significant negative correlation between fluorescence intensity and the dosage when the concentration of Dex was less than25μmol·L-1. Ver can increase the fluorescence intensity in a dose-dependent manner.
The study of expression of P-gp showed that there was no difference between Dex group(within0.01～0.1μmol·L-1) and control group in the fluorescence (P>0.05). When the concentration of Dex was within1～50μmol·L-1, the fluorescence of Dex group was significantly higher than that of control group (P<0.05); When the concentration of Ver was within0.1～50μmol·L-1, the fluorescence of Ver group was significantly higher than that of control group (P<0.05).
3. The study of monolayer model showed that Ami and Nor are the poor substrates of P-glycoprotein and the efflux ratio of Ami and Nor were increased about10to60percents in presence of Dex and decreased about10to20percents in presence of Ver.
4. Dex can decrease the value of AUC of brain tissue in mice about40to50percent and Ver increased the AUC about10to50percents. There were no differences in Cmax between Dex group, Ver group and control group.
Conclusion
Dex can induce the function and the expression of P-gp, and Ver can inhibit the function and induce the expression of P-glycoprotein. Ami and Nor both are the poor substrates of P-gp. The efflux ratio of Ami and Nor can be increased by Dex and decreased by Ver. Results in vivo showed that distribution of Ami and Nor into the brain was increased by Ver and decreased by Dex.
The studies showed that the results in vitro can predict the outcomes of drug-drug interactions in central nervous system. Inducer and inhibitor can modulate the function and expression of P-glycoprotein, which indicates that rational use inducer and inhibitor can improve the curative effect and decrease adverse reactions.
引文
[1]Hanley MJ, Cancalon P, Widmer WW, et al. The effect of grapefruit juice on drug disposition[J]. Expert Opin Drug Metab Toxicol,2011,7(3):267-286.
[2]Ward LS. The difficult patient:drug interaction and the influence of concomitant diseases on the treatment of hypothyroidism[J]. Arq Bras Endocrinol Metabol, 2010,54(5):435-442.
[3]Levin TT, Cortes-Ladino A, Weiss M, et al. Life-threatening serotonin toxicity due to a citalopram-fluconazole drug interaction:case reports and discussion[J]. Gen Hosp Psychiatry,2008,30(4):372-377.
[4]Forget P, de Waroux B lP, Wallemacq P, et al. Life-threatening dextromethorphan intoxication associated with interaction with amitriptyline in a poor CYP2D6 metabolizer:a single case re-exposure study [J]. J Pain Symptom Manage, 2008,36(1):92-96.
[5]Kotb R, Vincent I, Dulioust A, et al. Life-threatening interaction between antiretroviral therapy and vinblastine in HIV-associated multicentric Castleman's disease[J]. Eur J Haematol,2006,76(3):269-271.
[6]Chiang HM, Fang SH, Wen KC, et al. Life-threatening interaction between the root extract of Pueraria lobata and methotrexate in rats[J]. Toxicol Appl Pharmacol,2005,209(3):263-268.
[7]Vethe NT, Midtvedt K, Asberg A, et al. [Drug interactions and immunosuppression in organ transplant recipients][J]. Tidsskr Nor Laegeforen, 2011,131(20):2000-2003.
[8]Bai JP. Ongoing challenges in drug interaction safety:from exposure to pharmacogenomics[J]. Drug Metab Pharmacokinet,2010,25(1):62-71.
[9]Lee SS, Zhang B, He ML, et al. Screening of active ingredients of herbal medicine for interaction with CYP450 3A4[J]. Phytother Res, 2007,21(11):1096-1099.
[10]Venkatakrishnan K, Obach RS, Rostami-Hodjegan A. Mechanism-based inactivation of human cytochrome P450 enzymes:strategies for diagnosis and drug-drug interaction risk assessment [J]. Xenobiotica,2007,37(10-11): 1225-1256.
[11]Aszalos A. Drug-drug interactions affected by the transporter protein, P-glycoprotein (ABCB1, MDR1)Ⅱ. Clinical aspects[J]. Drug Discov Today, 2007,12(19-20):838-843.
[12]Ramenskaia GV, Fainshtein SL, Sychev DA. [The role of changes in the functional activity and the amount of p-glycoprotein in drug pharmacokinetics][J]. Eksp Klin Farmakol,2007,70(1):72-80.
[13]Hayashi M, Tomita M. Mechanistic analysis for drug permeation through intestinal membrane[J]. Drug Metab Pharmacokinet,2007,22(2):67-77.
[14]Kock K, Grube M, Jedlitschky G, et al. Expression of adenosine triphosphate-binding cassette (ABC) drug transporters in peripheral blood cells: relevance for physiology and pharmacotherapy[J]. Clin Pharmacokinet, 2007,46(6):449-470.
[15]戴立波,方平飞,李焕德.P-gp调节对药物代谢动力学及药效学的影响[J].中南药学,2011,(08)：612-615.
[16]Vourvahis M, Kashuba AD. Mechanisms of pharmacokinetic and pharmacodynamic drug interactions associated with ritonavir-enhanced tipranavir[J]. Pharmacotherapy,2007,27(6):888-909.
[17]Zhou SF, Zhou ZW, Li CG, et al. Identification of drugs that interact with herbs in drug development[J]. Drug Discov Today,2007,12(15-16):664-673.
[18]Kakuda TN, Scholler-Gyure M, Hoetelmans RM. Pharmacokinetic interactions between etravirine and non-antiretroviral drugs [J]. Clin Pharmacokinet,2011, 50(1):25-39.
[19]Moons T, de Roo M, Claes S, et al. Relationship between P-glycoprotein and second-generation antipsychotics[J]. Pharmacogenomics,2011,12(8):1193-1211.
[20]杨少林,李焕德,彭珍珍,等.由P-糖蛋白介导的药物相互作用研究进展[J].中国医院用药评价与分析,2011,(06)：494-497.
[21]沈沅,李焕德.P-糖蛋白介导的中枢神经系统药物相互作用[J].中国临床药理学杂志,2008,(06)：533-538.
[22]Abaut AY, Chevanne F, Le CP. Oral bioavailability and intestinal secretion of amitriptyline:Role of P-glycoprotein?[J]. Int J Pharm,2007,330(1-2):121-128.
[23]Uhr M, Steckler T, Yassouridis A, et al. Penetration of amitriptyline, but not of fluoxetine, into brain is enhanced in mice with blood-brain barrier deficiency due to mdrla P-glycoprotein gene disruption[J]. Neuropsychopharmacology, 2000,22(4):380-387.
[24]Grauer MT, Uhr M. P-glycoprotein reduces the ability of amitriptyline metabolites to cross the blood brain barrier in mice after a 10-day administration of amitriptyline [J]. J Psychopharmacol,2004,18(1):66-74.
[25]Uhr M, Grauer MT, Yassouridis A, et al. Blood-brain barrier penetration and pharmacokinetics of amitriptyline and its metabolites in p-glycoprotein (abcblab) knock-out mice and controls[J]. J Psychiatr Res,2007,41(1-2):179-188.
[26]Hisaka A, Ohno Y, Yamamoto T, et al. Prediction of pharmacokinetic drug-drug interaction caused by changes in cytochrome P450 activity using in vivo information[J]. Pharmacol Ther,2010,125(2):230-248.
[27]Foti RS, Wienkers LC, Wahlstrom JL. Application of cytochrome P450 drug interaction screening in drug discovery [J]. Comb Chem High Throughput Screen, 2010,13(2):145-158.
[28]Hasegawa M, Kapelyukh Y, Tahara H, et al. Quantitative prediction of human pregnane X receptor and cytochrome P450 3A4 mediated drug-drug interaction in a novel multiple humanized mouse line[J]. Mol Pharmacol,2011,80(3):518-528.
[29]Grime KH, Bird J, Ferguson D, et al. Mechanism-based inhibition of cytochrome P450 enzymes:an evaluation of early decision making in vitro approaches and drug-drug interaction prediction methods[J]. Eur J Pharm Sci, 2009,36(2-3):175-191.
[30]Huang SM, Strong JM, Zhang L, et al. New era in drug interaction evaluation: US Food and Drug Administration update on CYP enzymes, transporters, and the guidance process[J]. J Clin Pharmacol,2008,48(6):662-670.
[31]Watanabe T, Kusuhara H, Watanabe T, et al. Prediction of the overall renal tubular secretion and hepatic clearance of anionic drugs and a renal drug-drug interaction involving organic anion transporter 3 in humans by in vitro uptake experiments[J]. Drug Metab Dispos,2011,39(6):1031-1038.
[32]Miners JO, Mackenzie PI, Knights KM. The prediction of drug-glucuronidation parameters in humans:UDP-glucuronosyltransferase enzyme-selective substrate and inhibitor probes for reaction phenotyping and in vitro-in vivo extrapolation of drug clearance and drug-drug interaction potential[J]. Drug Metab Rev, 2010,42(1):196-208.
[33]Gaillard Y, Breuil R, Doche C, et al. Detection of amitriptyline, nortriptyline and bromazepam in liver, CSF and hair in the homicidal poisoning of a one-month-old girl autopsied 8 months after death[J]. Forensic Sci Int, 2011,207(1-3):e16-18.
[34]Shen Y, Zhu RH, Li HD, et al. Validated LC-MS (ESI) assay for the simultaneous determination of amitriptyline and its metabolite nortriptyline in rat plasma: application to a pharmacokinetic comparison[J]. J Pharm Biomed Anal,2010, 53(3):735-739.
[35]Patel S, Patel NJ. Spectrophotometric and chromatographic simultaneous estimation of amitriptyline hydrochloride and chlordiazepoxide in tablet dosage forms[J]. Indian J Pharm Sci,2009,71(4):472-476.
[36]Desrosiers NA, Watterson JH, Dean D, et al. Detection of Amitriptyline, Citalopram, and Metabolites in Porcine Bones Following Extended Outdoor Decomposition* LID-10.1111/j.1556-4029.2011.01994.x [doi]
[37]陈昕,邓焕珍,叶维雅.大剂量阿米替林、苯巴比妥联合中毒1例分析[J].临床医学工程,2008,(10)：54-55.
[38]Munic V, Kelneric Z, Mikac L, et al. Differences in assessment of macrolide interaction with human MDR1 (ABCB1, P-gp) using rhodamine-123 efflux, ATPase activity and cellular accumulation assays[J]. Eur J Pharm Sci, 2010,41(1):86-95.
[39]He Y, Liu Y, Zeng S. Stereoselective and multiple carrier-mediated transport of cetirizine across Caco-2 cell monolayers with potential drug interaction[J]. Chirality,2010,22(7):684-692.
[40]Cho YA, Choi JS, Burm JP. Effects of the antioxidant baicalein on the pharmacokinetics of nimodipine in rats:a possible role of P-glycoprotein and CYP3A4 inhibition by baicalein[J]. Pharmacol Rep,2011,63(4):1066-1073.
[41]Yoo HH, Lee M, Lee MW, et al. Effects of Schisandra lignans on P-glycoprotein-mediated drug efflux in human intestinal Caco-2 [J]. Planta Med, 2007,73(5):444-450.
[42]陆博.羟基磷灰石/聚DL-乳酸复合内固定材料对成骨细胞活性影响的体外研究[J].中国生物医学工程学报,2003,(04)：350-357.
[43]周龙书.卵巢恶性肿瘤患者腹水中NK细胞活性及T淋巴细胞亚群的改变[J].第一军医大学学报,1999,(04)：312-314.
[44]魏爱青,李兴文,连秀珍,等.苍耳子药物血清对人肝癌细胞增殖的抑制作用[J].生态科学,2011,(06)：647-649.
[45]王琛,李玉珍,王晓扔,等.西洋参茎叶总皂苷通过抑制过度内质网应激减轻大鼠心肌细胞缺氧/复氧损伤[J].中国病理生理杂志,2012,(01)：22-28.
[46]Mitra P, Audus K, Williams G, et al. A comprehensive study demonstrating that p-glycoprotein function is directlyaffected by changes in pH:Implications for intestinal pH and effects on drugabsorption.LID-10.1002/jps.22596 [doi]
[47]Fardel O, Lecureur V, Guillouzo A. Regulation by dexamethasone of P-glycoprotein expression in cultured rathepatocytes[J]. FEBS Lett,1993,327(2): 189-193.
[48]Perloff MD, von MLL, Greenblatt DJ. Ritonavir and dexamethasone induce expression of CYP3A and P-glycoprotein inrats[J]. Xenobiotica,2004,34(2): 133-150.
[49]Chieli E, Santoni-Rugiu E, Cervelli F, et al. Differential modulation of P-glycoprotein expression by dexamethasone and3-methylcholanthrene in rat hepatocyte primary cultures[J]. Carcinogenesis,1994,15(2):335-341.
[50]Granzotto M, Drigo I, Candussio L, et al. Rifampicin and verapamil induce the expression of P-glycoprotein in vivo in Ehrlich ascites tumor cells [J]. Cancer Lett, 2004,205(1):107-115.
[51]Ishri RK, Menzies S, Halliday GM. Verapamil induces upregulation of P-glycoprotein expression on human monocyte derived dendritic cells[J]. Immunol Invest,2006,35(1):1-18.
[52]Chieli E, Romiti N, Cervelli F, et al. Influence of rat strain on P-glycoprotein expression in cultured hepatocytes[J]. Cell Biol Toxicol,1994,10(3):163-166.
[53]Fardel O, Lecureur V, Guillouzo A. Regulation by dexamethasone of P-glycoprotein expression in cultured rathepatocytes[J]. FEBS Lett, 1993,327(2):189-193.
[54]Salphati L, Benet LZ. Modulation of P-glycoprotein expression by cytochrome P450 3A inducers in maleand female rat livers[J]. Biochem Pharmacol, 1998,55(4):387-395.
[55]马春燕.高效液相色谱法测定盐酸普萘洛尔片含量[J].中国药师,2005,8(8)：637-638.
[56]Ashiru-Oredope DA, Patel N, Forbes B, et al. The effect of polyoxyethylene polymers on the transport of ranitidine in Caco-2 cell monolayers[J]. Int J Pharm, 2011,409(1-2):164-168.
[57]Wang XD, Zeng S. The transport of gastrodin in Caco-2 cells and uptake in Bcap37 and Bcap37/MDR1 cells[J]. Yao Xue Xue Bao,2010,45(12):1497-1502.
[58]Hariharan S, Gunda S, Mishra GP, et al. Enhanced corneal absorption of erythromycin by modulating P-glycoprotein and MRP mediated efflux with corticosteroids[J]. Pharm Res,2009,26(5):1270-1282.
[59]Gillis NK, Zhu HJ, Markowitz JS. An in vitro evaluation of guanfacine as a substrate for P-glycoprotein[J]. Neuropsychiatr Dis Treat,2011,7:501-505.
[60]Zhu HJ, Wang JS, Markowitz JS, et al. Characterization of P-glycoprotein inhibition by major cannabinoids frommarijuana[J]. J Pharmacol Exp Ther, 2006,317(2):850-857.
[61]Liu W, Okochi H, Benet LZ, et al. Sotalol Permeability in Cultured-Cell, Rat Intestine, and PAMPA System[J]. Pharm Res,2012.
[62]Pick A, Wiese M. Tyrosine Kinase Inhibitors Influence ABCG2 Expression in EGFR-Positive MDCK BCRP Cells via the PI3K/Akt Signaling Pathway.LID 10.1002/cmdc.201100543 [doi]
[63]Korzekwa K, Nagar S, Tucker J, et al. Models to Predict Unbound Intracellular Drug Concentrations in the Presence ofTransporters[J]. Drug Metab Dispos, 2012.
[64]Zhu HJ, Wang JS, Donovan JL, et al. Interactions of attention-deficit/hyperactivity disorder therapeutic agents with the efflux transporter P-glycoprotein[J]. Eur J Pharmacol,2008,578(2-3):148-158.
[65]Uhr M, Grauer MT, Yassouridis A, et al. Blood-brain barrier penetration and pharmacokinetics of amitriptyline and its metabolites in p-glycoprotein (abcblab) knock-out mice and controls[J]. J Psychiatr Res,2007,41(1-2):179-188.
[66]Chieli E, Santoni-Rugiu E, Cervelli F, et al. Differential modulation of P-glycoprotein expression by dexamethasone and3-methylcholanthrene in rat hepatocyte primary cultures[J]. Carcinogenesis,1994,15(2):335-341.
[1]Girardin F. Membrane transporter proteins:a challenge for CNS drug development[J]. Dialogues Clin Neurosci,2006,8(3):311-321.
[2]Ito K, Uchida Y, Ohtsuki S, et al. Quantitative membrane protein expression at the blood-brain barrier of adult and younger cynomolgus monkeys [J]. J Pharm Sci,2011. Pharm Sci.2011,100(9):3939-3950.
[3]Guo Z, Zhu J, Zhao L, et al. Expression and clinical significance of multidrug resistance proteins in brain tumors[J]. J Exp Clin Cancer Res,2010,29:122.
[4]Potschka H. Targeting the brain--surmounting or bypassing the blood-brain barrier[J]. Handb Exp Pharmacol,2010,(197):411-431.
[5]Leslie EM, Deeley RG, Cole SP. Multidrug resistance proteins:role of P-glycoprotein, MRP1, MRP2, and BCRP (ABCG2) in tissue defense[J]. Toxicol Appl Pharmacol,2005,204(3):216-237.
[6]Urquhart BL, Kim RB. Blood-brain barrier transporters and response to CNS-active drugs[J]. Eur J Clin Pharmacol,2009,65(11):1063-1070.
[7]Kirschbaum KM, Uhr M, Holthoewer D, et al. Pharmacokinetics of acute and sub-chronic aripiprazole in P-glycoprotein deficient mice[J]. Neuropharmacology, 2010,59(6):474-479.
[8]Sarginson JE, Lazzeroni LC, Ryan HS, et al. ABCB1 (MDR1) polymorphisms and antidepressant response in geriatric depression[J]. Pharmacogenet Genomics, 2010,20(8):467-475.
[9]Iqbal M, Gibb W, Matthews SG. Corticosteroid Regulation of P-Glycoprotein in the Developing Blood-Brain Barrier[J]. Endocrinology,2011,152(3):1067-1079.
[10]Hartz AM, Mahringer A, Miller DS, et al.17-beta-Estradiol:a powerful modulator of blood-brain barrier BCRP activity [J]. J Cereb Blood Flow Metab, 2010,30(10):1742-1755.
[11]Kannan P, Brimacombe KR, Zoghbi SS, et al. N-desmethyl-loperamide is selective for P-glycoprotein among three ATP-binding cassette transporters at the blood-brain barrier[J]. Drug Metab Dispos,2010,38(6):917-922.
[12]Ek CJ, Wong A, Liddelow SA, et al. Efflux mechanisms at the developing brain barriers:ABC-transporters in the fetal and postnatal rat[J]. Toxicol Lett, 2010,197(1):51-59.
[13]Milane A, Vautier S, Chacun H, et al. Interactions between riluzole and ABCG2/BCRP transporter[J]. Neurosci Lett,2009,452(1):12-16.
[14]de Vries NA, Zhao J, Kroon E, et al. P-glycoprotein and breast cancer resistance protein:two dominant transporters working together in limiting the brain penetration of topotecan[J]. Clin Cancer Res,2007,13(21):6440-6449.
[15]Zhao R, Raub TJ, Sawada GA, et al. Breast cancer resistance protein interacts with various compounds in vitro, but plays a minor role in substrate efflux at the blood-brain barrier[J]. Drug Metab Dispos,2009,37(6):1251-1258.
[16]Zhou SF, Wang LL, Di YM, et al. Substrates and inhibitors of human multidrug resistance associated proteins and the implications in drug development J]. Curr Med Chem,2008,15(20):1981-2039.
[17]Park S, Sinko PJ. P-glycoprotein and mutlidrug resistance-associated proteins limit the brain uptake of saquinavir in mice[J]. J Pharmacol Exp Ther, 2005,312(3):1249-1256.
[18]Lin CJ, Tai Y, Huang MT, et al. Cellular localization of the organic cation transporters, OCT1 and OCT2, in brain micro vessel endothelial cells and its implication for MPTP transport across the blood-brain barrier and MPTP-induced dopaminergic toxicity in rodents[J]. J Neurochem,2010,114(3):717-727.
[19]Uhernik AL, Tucker C, Smith JP. Control of MCT1 function in cerebrovascular endothelial cells by intracellular pH[J]. Brain Res,2011.1376(2):10-12
[20]Lauritzen F, de Lanerolle NC, Lee TS, et al. Monocarboxylate transporter 1 is deficient on microvessels in the human epileptogenic hippocampus [J]. Neurobiol Dis,2011,41(2):577-584.
[2]Ward LS. The difficult patient:drug interaction and the influence of concomitant diseases on the treatment of hypothyroidism[J]. Arq Bras Endocrinol Metabol, 2010,54(5):435-442.
[3]Levin TT, Cortes-Ladino A, Weiss M, et al. Life-threatening serotonin toxicity due to a citalopram-fluconazole drug interaction:case reports and discussion[J]. Gen Hosp Psychiatry,2008,30(4):372-377.
[4]Forget P, de Waroux B lP, Wallemacq P, et al. Life-threatening dextromethorphan intoxication associated with interaction with amitriptyline in a poor CYP2D6 metabolizer:a single case re-exposure study [J]. J Pain Symptom Manage, 2008,36(1):92-96.
[5]Kotb R, Vincent I, Dulioust A, et al. Life-threatening interaction between antiretroviral therapy and vinblastine in HIV-associated multicentric Castleman's disease[J]. Eur J Haematol,2006,76(3):269-271.
[6]Chiang HM, Fang SH, Wen KC, et al. Life-threatening interaction between the root extract of Pueraria lobata and methotrexate in rats[J]. Toxicol Appl Pharmacol,2005,209(3):263-268.
[7]Vethe NT, Midtvedt K, Asberg A, et al. [Drug interactions and immunosuppression in organ transplant recipients][J]. Tidsskr Nor Laegeforen, 2011,131(20):2000-2003.
[8]Bai JP. Ongoing challenges in drug interaction safety:from exposure to pharmacogenomics[J]. Drug Metab Pharmacokinet,2010,25(1):62-71.
[9]Lee SS, Zhang B, He ML, et al. Screening of active ingredients of herbal medicine for interaction with CYP450 3A4[J]. Phytother Res, 2007,21(11):1096-1099.
[10]Venkatakrishnan K, Obach RS, Rostami-Hodjegan A. Mechanism-based inactivation of human cytochrome P450 enzymes:strategies for diagnosis and drug-drug interaction risk assessment [J]. Xenobiotica,2007,37(10-11): 1225-1256.
[11]Aszalos A. Drug-drug interactions affected by the transporter protein, P-glycoprotein (ABCB1, MDR1)Ⅱ. Clinical aspects[J]. Drug Discov Today, 2007,12(19-20):838-843.
[12]Ramenskaia GV, Fainshtein SL, Sychev DA. [The role of changes in the functional activity and the amount of p-glycoprotein in drug pharmacokinetics][J]. Eksp Klin Farmakol,2007,70(1):72-80.
[13]Hayashi M, Tomita M. Mechanistic analysis for drug permeation through intestinal membrane[J]. Drug Metab Pharmacokinet,2007,22(2):67-77.
[14]Kock K, Grube M, Jedlitschky G, et al. Expression of adenosine triphosphate-binding cassette (ABC) drug transporters in peripheral blood cells: relevance for physiology and pharmacotherapy[J]. Clin Pharmacokinet, 2007,46(6):449-470.
[15]戴立波,方平飞,李焕德.P-gp调节对药物代谢动力学及药效学的影响[J].中南药学,2011,(08)：612-615.
[16]Vourvahis M, Kashuba AD. Mechanisms of pharmacokinetic and pharmacodynamic drug interactions associated with ritonavir-enhanced tipranavir[J]. Pharmacotherapy,2007,27(6):888-909.
[17]Zhou SF, Zhou ZW, Li CG, et al. Identification of drugs that interact with herbs in drug development[J]. Drug Discov Today,2007,12(15-16):664-673.
[18]Kakuda TN, Scholler-Gyure M, Hoetelmans RM. Pharmacokinetic interactions between etravirine and non-antiretroviral drugs [J]. Clin Pharmacokinet,2011, 50(1):25-39.
[19]Moons T, de Roo M, Claes S, et al. Relationship between P-glycoprotein and second-generation antipsychotics[J]. Pharmacogenomics,2011,12(8):1193-1211.
[20]杨少林,李焕德,彭珍珍,等.由P-糖蛋白介导的药物相互作用研究进展[J].中国医院用药评价与分析,2011,(06)：494-497.
[21]沈沅,李焕德.P-糖蛋白介导的中枢神经系统药物相互作用[J].中国临床药理学杂志,2008,(06)：533-538.
[22]Abaut AY, Chevanne F, Le CP. Oral bioavailability and intestinal secretion of amitriptyline:Role of P-glycoprotein?[J]. Int J Pharm,2007,330(1-2):121-128.
[23]Uhr M, Steckler T, Yassouridis A, et al. Penetration of amitriptyline, but not of fluoxetine, into brain is enhanced in mice with blood-brain barrier deficiency due to mdrla P-glycoprotein gene disruption[J]. Neuropsychopharmacology, 2000,22(4):380-387.
[24]Grauer MT, Uhr M. P-glycoprotein reduces the ability of amitriptyline metabolites to cross the blood brain barrier in mice after a 10-day administration of amitriptyline [J]. J Psychopharmacol,2004,18(1):66-74.
[25]Uhr M, Grauer MT, Yassouridis A, et al. Blood-brain barrier penetration and pharmacokinetics of amitriptyline and its metabolites in p-glycoprotein (abcblab) knock-out mice and controls[J]. J Psychiatr Res,2007,41(1-2):179-188.
[26]Hisaka A, Ohno Y, Yamamoto T, et al. Prediction of pharmacokinetic drug-drug interaction caused by changes in cytochrome P450 activity using in vivo information[J]. Pharmacol Ther,2010,125(2):230-248.
[27]Foti RS, Wienkers LC, Wahlstrom JL. Application of cytochrome P450 drug interaction screening in drug discovery [J]. Comb Chem High Throughput Screen, 2010,13(2):145-158.
[28]Hasegawa M, Kapelyukh Y, Tahara H, et al. Quantitative prediction of human pregnane X receptor and cytochrome P450 3A4 mediated drug-drug interaction in a novel multiple humanized mouse line[J]. Mol Pharmacol,2011,80(3):518-528.
[29]Grime KH, Bird J, Ferguson D, et al. Mechanism-based inhibition of cytochrome P450 enzymes:an evaluation of early decision making in vitro approaches and drug-drug interaction prediction methods[J]. Eur J Pharm Sci, 2009,36(2-3):175-191.
[30]Huang SM, Strong JM, Zhang L, et al. New era in drug interaction evaluation: US Food and Drug Administration update on CYP enzymes, transporters, and the guidance process[J]. J Clin Pharmacol,2008,48(6):662-670.
[31]Watanabe T, Kusuhara H, Watanabe T, et al. Prediction of the overall renal tubular secretion and hepatic clearance of anionic drugs and a renal drug-drug interaction involving organic anion transporter 3 in humans by in vitro uptake experiments[J]. Drug Metab Dispos,2011,39(6):1031-1038.
[32]Miners JO, Mackenzie PI, Knights KM. The prediction of drug-glucuronidation parameters in humans:UDP-glucuronosyltransferase enzyme-selective substrate and inhibitor probes for reaction phenotyping and in vitro-in vivo extrapolation of drug clearance and drug-drug interaction potential[J]. Drug Metab Rev, 2010,42(1):196-208.
[33]Gaillard Y, Breuil R, Doche C, et al. Detection of amitriptyline, nortriptyline and bromazepam in liver, CSF and hair in the homicidal poisoning of a one-month-old girl autopsied 8 months after death[J]. Forensic Sci Int, 2011,207(1-3):e16-18.
[34]Shen Y, Zhu RH, Li HD, et al. Validated LC-MS (ESI) assay for the simultaneous determination of amitriptyline and its metabolite nortriptyline in rat plasma: application to a pharmacokinetic comparison[J]. J Pharm Biomed Anal,2010, 53(3):735-739.
[35]Patel S, Patel NJ. Spectrophotometric and chromatographic simultaneous estimation of amitriptyline hydrochloride and chlordiazepoxide in tablet dosage forms[J]. Indian J Pharm Sci,2009,71(4):472-476.
[36]Desrosiers NA, Watterson JH, Dean D, et al. Detection of Amitriptyline, Citalopram, and Metabolites in Porcine Bones Following Extended Outdoor Decomposition* LID-10.1111/j.1556-4029.2011.01994.x [doi]
[37]陈昕,邓焕珍,叶维雅.大剂量阿米替林、苯巴比妥联合中毒1例分析[J].临床医学工程,2008,(10)：54-55.
[38]Munic V, Kelneric Z, Mikac L, et al. Differences in assessment of macrolide interaction with human MDR1 (ABCB1, P-gp) using rhodamine-123 efflux, ATPase activity and cellular accumulation assays[J]. Eur J Pharm Sci, 2010,41(1):86-95.
[39]He Y, Liu Y, Zeng S. Stereoselective and multiple carrier-mediated transport of cetirizine across Caco-2 cell monolayers with potential drug interaction[J]. Chirality,2010,22(7):684-692.
[40]Cho YA, Choi JS, Burm JP. Effects of the antioxidant baicalein on the pharmacokinetics of nimodipine in rats:a possible role of P-glycoprotein and CYP3A4 inhibition by baicalein[J]. Pharmacol Rep,2011,63(4):1066-1073.
[41]Yoo HH, Lee M, Lee MW, et al. Effects of Schisandra lignans on P-glycoprotein-mediated drug efflux in human intestinal Caco-2 [J]. Planta Med, 2007,73(5):444-450.
[42]陆博.羟基磷灰石/聚DL-乳酸复合内固定材料对成骨细胞活性影响的体外研究[J].中国生物医学工程学报,2003,(04)：350-357.
[43]周龙书.卵巢恶性肿瘤患者腹水中NK细胞活性及T淋巴细胞亚群的改变[J].第一军医大学学报,1999,(04)：312-314.
[44]魏爱青,李兴文,连秀珍,等.苍耳子药物血清对人肝癌细胞增殖的抑制作用[J].生态科学,2011,(06)：647-649.
[45]王琛,李玉珍,王晓扔,等.西洋参茎叶总皂苷通过抑制过度内质网应激减轻大鼠心肌细胞缺氧/复氧损伤[J].中国病理生理杂志,2012,(01)：22-28.
[46]Mitra P, Audus K, Williams G, et al. A comprehensive study demonstrating that p-glycoprotein function is directlyaffected by changes in pH:Implications for intestinal pH and effects on drugabsorption.LID-10.1002/jps.22596 [doi]
[47]Fardel O, Lecureur V, Guillouzo A. Regulation by dexamethasone of P-glycoprotein expression in cultured rathepatocytes[J]. FEBS Lett,1993,327(2): 189-193.
[48]Perloff MD, von MLL, Greenblatt DJ. Ritonavir and dexamethasone induce expression of CYP3A and P-glycoprotein inrats[J]. Xenobiotica,2004,34(2): 133-150.
[49]Chieli E, Santoni-Rugiu E, Cervelli F, et al. Differential modulation of P-glycoprotein expression by dexamethasone and3-methylcholanthrene in rat hepatocyte primary cultures[J]. Carcinogenesis,1994,15(2):335-341.
[50]Granzotto M, Drigo I, Candussio L, et al. Rifampicin and verapamil induce the expression of P-glycoprotein in vivo in Ehrlich ascites tumor cells [J]. Cancer Lett, 2004,205(1):107-115.
[51]Ishri RK, Menzies S, Halliday GM. Verapamil induces upregulation of P-glycoprotein expression on human monocyte derived dendritic cells[J]. Immunol Invest,2006,35(1):1-18.
[52]Chieli E, Romiti N, Cervelli F, et al. Influence of rat strain on P-glycoprotein expression in cultured hepatocytes[J]. Cell Biol Toxicol,1994,10(3):163-166.
[53]Fardel O, Lecureur V, Guillouzo A. Regulation by dexamethasone of P-glycoprotein expression in cultured rathepatocytes[J]. FEBS Lett, 1993,327(2):189-193.
[54]Salphati L, Benet LZ. Modulation of P-glycoprotein expression by cytochrome P450 3A inducers in maleand female rat livers[J]. Biochem Pharmacol, 1998,55(4):387-395.
[55]马春燕.高效液相色谱法测定盐酸普萘洛尔片含量[J].中国药师,2005,8(8)：637-638.
[56]Ashiru-Oredope DA, Patel N, Forbes B, et al. The effect of polyoxyethylene polymers on the transport of ranitidine in Caco-2 cell monolayers[J]. Int J Pharm, 2011,409(1-2):164-168.
[57]Wang XD, Zeng S. The transport of gastrodin in Caco-2 cells and uptake in Bcap37 and Bcap37/MDR1 cells[J]. Yao Xue Xue Bao,2010,45(12):1497-1502.
[58]Hariharan S, Gunda S, Mishra GP, et al. Enhanced corneal absorption of erythromycin by modulating P-glycoprotein and MRP mediated efflux with corticosteroids[J]. Pharm Res,2009,26(5):1270-1282.
[59]Gillis NK, Zhu HJ, Markowitz JS. An in vitro evaluation of guanfacine as a substrate for P-glycoprotein[J]. Neuropsychiatr Dis Treat,2011,7:501-505.
[60]Zhu HJ, Wang JS, Markowitz JS, et al. Characterization of P-glycoprotein inhibition by major cannabinoids frommarijuana[J]. J Pharmacol Exp Ther, 2006,317(2):850-857.
[61]Liu W, Okochi H, Benet LZ, et al. Sotalol Permeability in Cultured-Cell, Rat Intestine, and PAMPA System[J]. Pharm Res,2012.
[62]Pick A, Wiese M. Tyrosine Kinase Inhibitors Influence ABCG2 Expression in EGFR-Positive MDCK BCRP Cells via the PI3K/Akt Signaling Pathway.LID 10.1002/cmdc.201100543 [doi]
[63]Korzekwa K, Nagar S, Tucker J, et al. Models to Predict Unbound Intracellular Drug Concentrations in the Presence ofTransporters[J]. Drug Metab Dispos, 2012.
[64]Zhu HJ, Wang JS, Donovan JL, et al. Interactions of attention-deficit/hyperactivity disorder therapeutic agents with the efflux transporter P-glycoprotein[J]. Eur J Pharmacol,2008,578(2-3):148-158.
[65]Uhr M, Grauer MT, Yassouridis A, et al. Blood-brain barrier penetration and pharmacokinetics of amitriptyline and its metabolites in p-glycoprotein (abcblab) knock-out mice and controls[J]. J Psychiatr Res,2007,41(1-2):179-188.
[66]Chieli E, Santoni-Rugiu E, Cervelli F, et al. Differential modulation of P-glycoprotein expression by dexamethasone and3-methylcholanthrene in rat hepatocyte primary cultures[J]. Carcinogenesis,1994,15(2):335-341.
[1]Girardin F. Membrane transporter proteins:a challenge for CNS drug development[J]. Dialogues Clin Neurosci,2006,8(3):311-321.
[2]Ito K, Uchida Y, Ohtsuki S, et al. Quantitative membrane protein expression at the blood-brain barrier of adult and younger cynomolgus monkeys [J]. J Pharm Sci,2011. Pharm Sci.2011,100(9):3939-3950.
[3]Guo Z, Zhu J, Zhao L, et al. Expression and clinical significance of multidrug resistance proteins in brain tumors[J]. J Exp Clin Cancer Res,2010,29:122.
[4]Potschka H. Targeting the brain--surmounting or bypassing the blood-brain barrier[J]. Handb Exp Pharmacol,2010,(197):411-431.
[5]Leslie EM, Deeley RG, Cole SP. Multidrug resistance proteins:role of P-glycoprotein, MRP1, MRP2, and BCRP (ABCG2) in tissue defense[J]. Toxicol Appl Pharmacol,2005,204(3):216-237.
[6]Urquhart BL, Kim RB. Blood-brain barrier transporters and response to CNS-active drugs[J]. Eur J Clin Pharmacol,2009,65(11):1063-1070.
[7]Kirschbaum KM, Uhr M, Holthoewer D, et al. Pharmacokinetics of acute and sub-chronic aripiprazole in P-glycoprotein deficient mice[J]. Neuropharmacology, 2010,59(6):474-479.
[8]Sarginson JE, Lazzeroni LC, Ryan HS, et al. ABCB1 (MDR1) polymorphisms and antidepressant response in geriatric depression[J]. Pharmacogenet Genomics, 2010,20(8):467-475.
[9]Iqbal M, Gibb W, Matthews SG. Corticosteroid Regulation of P-Glycoprotein in the Developing Blood-Brain Barrier[J]. Endocrinology,2011,152(3):1067-1079.
[10]Hartz AM, Mahringer A, Miller DS, et al.17-beta-Estradiol:a powerful modulator of blood-brain barrier BCRP activity [J]. J Cereb Blood Flow Metab, 2010,30(10):1742-1755.
[11]Kannan P, Brimacombe KR, Zoghbi SS, et al. N-desmethyl-loperamide is selective for P-glycoprotein among three ATP-binding cassette transporters at the blood-brain barrier[J]. Drug Metab Dispos,2010,38(6):917-922.
[12]Ek CJ, Wong A, Liddelow SA, et al. Efflux mechanisms at the developing brain barriers:ABC-transporters in the fetal and postnatal rat[J]. Toxicol Lett, 2010,197(1):51-59.
[13]Milane A, Vautier S, Chacun H, et al. Interactions between riluzole and ABCG2/BCRP transporter[J]. Neurosci Lett,2009,452(1):12-16.
[14]de Vries NA, Zhao J, Kroon E, et al. P-glycoprotein and breast cancer resistance protein:two dominant transporters working together in limiting the brain penetration of topotecan[J]. Clin Cancer Res,2007,13(21):6440-6449.
[15]Zhao R, Raub TJ, Sawada GA, et al. Breast cancer resistance protein interacts with various compounds in vitro, but plays a minor role in substrate efflux at the blood-brain barrier[J]. Drug Metab Dispos,2009,37(6):1251-1258.
[16]Zhou SF, Wang LL, Di YM, et al. Substrates and inhibitors of human multidrug resistance associated proteins and the implications in drug development J]. Curr Med Chem,2008,15(20):1981-2039.
[17]Park S, Sinko PJ. P-glycoprotein and mutlidrug resistance-associated proteins limit the brain uptake of saquinavir in mice[J]. J Pharmacol Exp Ther, 2005,312(3):1249-1256.
[18]Lin CJ, Tai Y, Huang MT, et al. Cellular localization of the organic cation transporters, OCT1 and OCT2, in brain micro vessel endothelial cells and its implication for MPTP transport across the blood-brain barrier and MPTP-induced dopaminergic toxicity in rodents[J]. J Neurochem,2010,114(3):717-727.
[19]Uhernik AL, Tucker C, Smith JP. Control of MCT1 function in cerebrovascular endothelial cells by intracellular pH[J]. Brain Res,2011.1376(2):10-12
[20]Lauritzen F, de Lanerolle NC, Lee TS, et al. Monocarboxylate transporter 1 is deficient on microvessels in the human epileptogenic hippocampus [J]. Neurobiol Dis,2011,41(2):577-584.
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