坎地沙坦西酯片人体药动学和生物等效性及坎地沙坦吸收机制的研究
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摘要
坎地沙坦(Candesartan,CDS)是一种新型的作用于肾素.醛固酮系统的抗高血压药物,它对血管紧张素Ⅱ1型受体有强亲和力,可选择性地阻断该受体的作用,从而阻断血管紧张素Ⅱ的血管收缩作用,减少醛固酮分泌,达到降压效果。由于CDS口服吸收差,临床应用多为其前体药物——坎地沙坦西酯(Candesartan Cilexetil,CC),CC在胃肠道吸收过程中迅速完全转化为CDS。CC用于治疗原发性高血压、心力衰竭、高血压合并左心室肥厚、糖尿病肾病等多种疾病,疗效肯定。本课题建立了人血清中CDS的高效液相.荧光检测(HPLC-Flu)方法,用该方法考察了中国健康男性志愿者口服8 mg CC片后的药动学参数,并对两种制剂的生物等效性进行了评价;另外还应用Caco-2细胞模型和大鼠在体肠吸收模型对CDS的吸收机制进行了初步研究。
课题的第一部分建立和验证了HPLC-Flu测定人血清中CDS浓度的方法。以萘普生为内标(I.S),血清用液.液萃取进行处理。色谱柱:YMC~(?)ODS柱(250mm×4.6mm,5μn);柱温:30℃;流动相:10mmol/L磷酸二氢钾溶液(磷酸调pH为3.0):乙腈=60:40(V/V);流速:1.0mL/min;荧光检测波长:激发波长270nm,发射波长390nm;进样量:20μL。血清内源性杂质对样品的测定没有干扰。CDS与I.S的色谱保留时间分别为10.4min和16.5min。CDS在1.01～202ng·mL~(-1)范围内线性良好(r=0.9998),最低定量浓度为1.01ng·mL~(-1)。CDS的日内、日间精密度和准确度良好,样品长期冻融(45天)和多次冻融(n=3)稳定性良好。该方法快速、灵敏、准确,可用于临床药动学及生物等效性研究。
课题的第二部分考察了中国健康男性志愿者口服8 mg CC片后的药动学参数,并对两种制剂的生物等效性进行了评价。20名受试者随机编号分为两组,交叉口服给药进行试验,血样测定采用第一部分建立的HPLC-Flu法。结果显示,20名健康男性志愿者单剂量口服CC试验片和参比片8mg后药动学参数分别为:AUC_(0-t)(ng·hr·mL~(-1)):943.94±382.60和923.67±350.39:AUC_(0-∞)(ng·hr·mL~(-1)):979.72±380.41和967.95±353.61;C_(max)(ng·mL~(-1)):90.36±40.45和91.52±39.69;T_(max)(h):3.98±1.26和4.13±0.60;t_(1/2)(h):10.18±1.26和10.43±2.58。统计结果显示:T_(max)经非参数统计(Wilcoxon检验),试验制剂与参比制剂之间无显著性差异;试验片和参比片的AUC_(0～t),AUC_(0-∞)o和C_(max)经多因素方差分析(ANOVA)无显著性差异。由双单侧t检验计算90%置信区间,试验片AUC_(0-t)的90%置信区间落在对照参比制剂的90.28%～113.90%范围内,AUC_(0-∞)的90%置信区间落在对照参比制剂的89.99%～112.25%范围内,C_(max)的90%置信区间落在对照参比制剂的86.03%～111.07%范围内,试验制剂与参比制剂生物等效。本实验得到的中国志愿者的药动学参数与文献报道的欧洲志愿者的参数基本吻合。CDS个体间药动学差异较大。
课题的第三部分考察了CDS在Caco-2细胞模型中的摄取及转运机制。研究结果表明,CDS在Caco-2细胞中的摄取主要为被动扩散的方式;在pH6.0-8.0的介质环境中,药物的摄取和转运无pH依赖性;不同浓度CDS的吸收表观通透系数Papp平均值为(2.18×10~(-6))cm·sec~(-1);加入P-糖蛋白(P-glycoprotein)抑制剂环孢素A和维拉帕米能显著地提高CDS的吸收,同时降低CDS的分泌,表明CDS的吸收过程可能受到P-gp的外排作用。
课题的第四部分考察了CDS在大鼠在体肠吸收模型中的吸收情况。结果显示,CDS在大鼠不同肠断(十二指肠、空肠、回肠)的吸收速率常数(Ka)和有效透皮系数(P_(eff))无显著性差异,说明CDS无特殊的吸收窗;浓度范围0.2～25μg·mL~(-1)的CDS在空肠段吸收的Ka和P_(eff)无显著差异,说明CDS的吸收机制为被动扩散;一些治疗心血管疾病药物联合给药不影响CDS在大鼠空肠的吸收。
Candesartan(CDS),a novel oral active non-peptide angiotensinⅡtype 1(AT_1) receptor blockor,is widely used in the treatment of hypertension.CDS has been developed to specifically and selectively block the AT_1 receptor of the rennin angiotensin system by displacing angiotensinⅡfrom it,which is responsible for the effects that include vasoconstriction,stimulation of synthesis and release of aldosterone,cardiac stimulation,and renal reabsorption of sodium.Because of its imcomplete absorption,CDS is administered as a pro-drug,Candesartan cilexetil (CC).CC is rapidly and completely hydrolyzed to active compound(CDS) from the gastrointestinal tract.CC is useful in the treatment of patients with essential hypertension,heart failure and may protect against diabetic nephropathy.Studies have also shown protection from stroke,particularly in patients with isolated systolic hypertension.In this paper,a sensitive and specific method for determination of CDS in human serum was developed,based on HPLC-Flu.The method was successfully used to investigate the pharmacokinetics and bioequivalence of CC tablets in Chinese healthy male volunteers.In addition,the absorption mechanism of CDS was studied with the model Caco-2 cell line and in situ intestinal absorptive model in rat.
A sensitive,simple,and accurate HPLC-Flu method was developed for the determination of CDS in human serum in the Section 1.Using naproxen as internal standard(I.S),CDS in serum was determined by HPLC with liquid-liquid extraction of the compound from acidified serum into organic solvent and was separated by the column of YMC~(?)ODS(250mm×4.6mm,5μm) at 30℃.The mobile phase consisted of a mixture 10mmol/L potassium dihydrogen phosphate solution(adjusted to pH 3.0 with phosphoric acid)-acetonitrile(60:40,V/V) pumped at a flow rate of 1.0mL/min. A fluorescence detector was set at an excitation wavelength of 270nm and an emission wavelength of 390nm.The drug-free serum did not interfere with the determination of CDS and I.S.There were good linear relationships(1/C~2 weighted,r=0.9998) between peak area ratio of CDS to I.S and C within the range of 1.01～202ng·mL~(-1).The lower limit of quantification was 1.01ng·mL~(-1).The precision of inter-and intra-day was less than 11%.CDS in serum was stable for at least 45 days and three freeze-thaw cycles. The method established in the paper can be applied to the clinical pharmacokinetics and bioequivalence study.
In the Section 2,the pharmacokinetics profiles of CC tablets(8mg) given in Chinese healthy male volunteers were investigated,and the bioequivalence of two kinds of CC tablets was evaluated.A single oral dose of 8mg CC of test tablet and reference one were given to 20 healthy volunteers in a double cross-over,controlled study.The CDS concentrations in serum were determined by the HPLC-Flu method developed in the Section 1.The AUC_(0-t),AUC_(0-∞),C_(max),T_(max) and t_(1/2) of test CC tablet and reference one were(943.94±382.60) and(923.67±350.39) ng·hr·mL~(-1), (979.72±380.41) and(967.95±353.61) ng·hr·mL~(-1),(90.36±40.45) and(91.52±39.69) ng·mL~(-1),(3.98±1.26) and(4.13±0.60) h,(10.18±1.26) and(10.43±2.58) h.The results of statistical analysis showed that two formulations were bioequivalent.The values of C_(max),T_(max) and t_(1/2) are almost consistent with the results obtained from European young healthy volunteers.It showed that pharmacokinetic parameters of CDS displayed large inter-individual variability in our study.
The Caco-2 cell model was used to study the uptake and transport mechanism of CDS in the Section 3.The results indicated:(1) The uptake and absorptive transport of CDS are passive diffusion.(2) The uptake and absorptive transport of CDS are pH independent in the range of pH6.0～8.0.(3) The mean absorptive Papp was estimated to be 2.18×10~(-6) cm·sec~(-1).(4) In the presence of Cyclosporin A and verapamil,potent inhibitor of P-glycoprotein,the permeation of AP-BL was enhanced and the permeation of BL-AP was decreased.It indicated that the polarized effiux of CDS in Caco-2 cell was probably due to the presence of P-gp.
In the Section 4,the intestinal transport of CDS was performed by applying single-pass intestinal perfusion technique in rat.The absorption of CDS was passive diffusion and had no significant difference in different gut regions(P＞0.05). Co-administration of some cardiovascular drugs had no adverse effect on the absorption of CDS.
课题的第一部分建立和验证了HPLC-Flu测定人血清中CDS浓度的方法。以萘普生为内标(I.S),血清用液.液萃取进行处理。色谱柱:YMC~(?)ODS柱(250mm×4.6mm,5μn);柱温:30℃;流动相:10mmol/L磷酸二氢钾溶液(磷酸调pH为3.0):乙腈=60:40(V/V);流速:1.0mL/min;荧光检测波长:激发波长270nm,发射波长390nm;进样量:20μL。血清内源性杂质对样品的测定没有干扰。CDS与I.S的色谱保留时间分别为10.4min和16.5min。CDS在1.01～202ng·mL~(-1)范围内线性良好(r=0.9998),最低定量浓度为1.01ng·mL~(-1)。CDS的日内、日间精密度和准确度良好,样品长期冻融(45天)和多次冻融(n=3)稳定性良好。该方法快速、灵敏、准确,可用于临床药动学及生物等效性研究。
课题的第二部分考察了中国健康男性志愿者口服8 mg CC片后的药动学参数,并对两种制剂的生物等效性进行了评价。20名受试者随机编号分为两组,交叉口服给药进行试验,血样测定采用第一部分建立的HPLC-Flu法。结果显示,20名健康男性志愿者单剂量口服CC试验片和参比片8mg后药动学参数分别为:AUC_(0-t)(ng·hr·mL~(-1)):943.94±382.60和923.67±350.39:AUC_(0-∞)(ng·hr·mL~(-1)):979.72±380.41和967.95±353.61;C_(max)(ng·mL~(-1)):90.36±40.45和91.52±39.69;T_(max)(h):3.98±1.26和4.13±0.60;t_(1/2)(h):10.18±1.26和10.43±2.58。统计结果显示:T_(max)经非参数统计(Wilcoxon检验),试验制剂与参比制剂之间无显著性差异;试验片和参比片的AUC_(0～t),AUC_(0-∞)o和C_(max)经多因素方差分析(ANOVA)无显著性差异。由双单侧t检验计算90%置信区间,试验片AUC_(0-t)的90%置信区间落在对照参比制剂的90.28%～113.90%范围内,AUC_(0-∞)的90%置信区间落在对照参比制剂的89.99%～112.25%范围内,C_(max)的90%置信区间落在对照参比制剂的86.03%～111.07%范围内,试验制剂与参比制剂生物等效。本实验得到的中国志愿者的药动学参数与文献报道的欧洲志愿者的参数基本吻合。CDS个体间药动学差异较大。
课题的第三部分考察了CDS在Caco-2细胞模型中的摄取及转运机制。研究结果表明,CDS在Caco-2细胞中的摄取主要为被动扩散的方式;在pH6.0-8.0的介质环境中,药物的摄取和转运无pH依赖性;不同浓度CDS的吸收表观通透系数Papp平均值为(2.18×10~(-6))cm·sec~(-1);加入P-糖蛋白(P-glycoprotein)抑制剂环孢素A和维拉帕米能显著地提高CDS的吸收,同时降低CDS的分泌,表明CDS的吸收过程可能受到P-gp的外排作用。
课题的第四部分考察了CDS在大鼠在体肠吸收模型中的吸收情况。结果显示,CDS在大鼠不同肠断(十二指肠、空肠、回肠)的吸收速率常数(Ka)和有效透皮系数(P_(eff))无显著性差异,说明CDS无特殊的吸收窗;浓度范围0.2～25μg·mL~(-1)的CDS在空肠段吸收的Ka和P_(eff)无显著差异,说明CDS的吸收机制为被动扩散;一些治疗心血管疾病药物联合给药不影响CDS在大鼠空肠的吸收。
Candesartan(CDS),a novel oral active non-peptide angiotensinⅡtype 1(AT_1) receptor blockor,is widely used in the treatment of hypertension.CDS has been developed to specifically and selectively block the AT_1 receptor of the rennin angiotensin system by displacing angiotensinⅡfrom it,which is responsible for the effects that include vasoconstriction,stimulation of synthesis and release of aldosterone,cardiac stimulation,and renal reabsorption of sodium.Because of its imcomplete absorption,CDS is administered as a pro-drug,Candesartan cilexetil (CC).CC is rapidly and completely hydrolyzed to active compound(CDS) from the gastrointestinal tract.CC is useful in the treatment of patients with essential hypertension,heart failure and may protect against diabetic nephropathy.Studies have also shown protection from stroke,particularly in patients with isolated systolic hypertension.In this paper,a sensitive and specific method for determination of CDS in human serum was developed,based on HPLC-Flu.The method was successfully used to investigate the pharmacokinetics and bioequivalence of CC tablets in Chinese healthy male volunteers.In addition,the absorption mechanism of CDS was studied with the model Caco-2 cell line and in situ intestinal absorptive model in rat.
A sensitive,simple,and accurate HPLC-Flu method was developed for the determination of CDS in human serum in the Section 1.Using naproxen as internal standard(I.S),CDS in serum was determined by HPLC with liquid-liquid extraction of the compound from acidified serum into organic solvent and was separated by the column of YMC~(?)ODS(250mm×4.6mm,5μm) at 30℃.The mobile phase consisted of a mixture 10mmol/L potassium dihydrogen phosphate solution(adjusted to pH 3.0 with phosphoric acid)-acetonitrile(60:40,V/V) pumped at a flow rate of 1.0mL/min. A fluorescence detector was set at an excitation wavelength of 270nm and an emission wavelength of 390nm.The drug-free serum did not interfere with the determination of CDS and I.S.There were good linear relationships(1/C~2 weighted,r=0.9998) between peak area ratio of CDS to I.S and C within the range of 1.01～202ng·mL~(-1).The lower limit of quantification was 1.01ng·mL~(-1).The precision of inter-and intra-day was less than 11%.CDS in serum was stable for at least 45 days and three freeze-thaw cycles. The method established in the paper can be applied to the clinical pharmacokinetics and bioequivalence study.
In the Section 2,the pharmacokinetics profiles of CC tablets(8mg) given in Chinese healthy male volunteers were investigated,and the bioequivalence of two kinds of CC tablets was evaluated.A single oral dose of 8mg CC of test tablet and reference one were given to 20 healthy volunteers in a double cross-over,controlled study.The CDS concentrations in serum were determined by the HPLC-Flu method developed in the Section 1.The AUC_(0-t),AUC_(0-∞),C_(max),T_(max) and t_(1/2) of test CC tablet and reference one were(943.94±382.60) and(923.67±350.39) ng·hr·mL~(-1), (979.72±380.41) and(967.95±353.61) ng·hr·mL~(-1),(90.36±40.45) and(91.52±39.69) ng·mL~(-1),(3.98±1.26) and(4.13±0.60) h,(10.18±1.26) and(10.43±2.58) h.The results of statistical analysis showed that two formulations were bioequivalent.The values of C_(max),T_(max) and t_(1/2) are almost consistent with the results obtained from European young healthy volunteers.It showed that pharmacokinetic parameters of CDS displayed large inter-individual variability in our study.
The Caco-2 cell model was used to study the uptake and transport mechanism of CDS in the Section 3.The results indicated:(1) The uptake and absorptive transport of CDS are passive diffusion.(2) The uptake and absorptive transport of CDS are pH independent in the range of pH6.0～8.0.(3) The mean absorptive Papp was estimated to be 2.18×10~(-6) cm·sec~(-1).(4) In the presence of Cyclosporin A and verapamil,potent inhibitor of P-glycoprotein,the permeation of AP-BL was enhanced and the permeation of BL-AP was decreased.It indicated that the polarized effiux of CDS in Caco-2 cell was probably due to the presence of P-gp.
In the Section 4,the intestinal transport of CDS was performed by applying single-pass intestinal perfusion technique in rat.The absorption of CDS was passive diffusion and had no significant difference in different gut regions(P＞0.05). Co-administration of some cardiovascular drugs had no adverse effect on the absorption of CDS.
引文
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[39]Lennernas H,Fagerholm M,Raab Y,et al.Reginal rectal perfusion,a new in vivo approach to study rectal drag absorption in man[J].Pharm Res.1995,12(3):426-432.
[40]关颖,杨涛,崔福德,等.运用单向灌流模型研究抗糖尿病创新药物西格列松大鼠在体肠的吸收[J].沈阳药科大学学报,2006,23(8):483-487.
[41]许英爱,范国荣,高申,等.山楂叶总黄酮的在体肠吸收研究[J].中成药,2007,29(12):1745-1748.
[42]McMurray JJV,Ostergren J,Swedberg K,et al.Effects of candesartan in patients with chronic heart failure and reduced left ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors:the CHARM-alternative trial,CHARM-added,CHARM-preserved[J].Lancet.2003,362(9386):767-781.
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[45]聂淑芳,潘卫三,杨星钢,等.对大鼠在体肠单向灌流技术中重量法的评价[J].中国新药杂志,2005,14(10):1176-1179.
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[1]Caldwell GW.Compound optimization in early- and late-phase drug discovery:Acceptable pharmacokinetic properties utilizing combined physicochemical,in vitro and in vivo screens[J].Current opinion in Drug Discovery & Development.2000,3(1):30-41.
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[3]Uchiyama T,Sugiyama T,Quan YS,et al.Enhanced permeability of insulin across the rat intestinal membrane by various absorption enhancers:their intestinal mucosal toxicity and absorption enhancing mechanism of n-lauryl-beta-D-maltopyranoside[J].J Pharm Pharmacol.1999,51:1241-1250.
[4]Leppert PS,Fix JA.Use of everted intestinal rings for in vitro examination of oral absorption potential[J].J Pharm Sci.1994,83:976-981.
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[1]Caldwell GW.Compound optimization in early- and late-phase drug discovery:Acceptable pharmacokinetic properties utilizing combined physicochemical,in vitro and in vivo screens[J].Current opinion in Drug Discovery & Development.2000,3(1):30-41.
[2]李高,方超.药物肠道吸收的生物学研究方法[J].中国药学杂志,2002,37(10):726-729.
[3]Uchiyama T,Sugiyama T,Quan YS,et al.Enhanced permeability of insulin across the rat intestinal membrane by various absorption enhancers:their intestinal mucosal toxicity and absorption enhancing mechanism of n-lauryl-beta-D-maltopyranoside[J].J Pharm Pharmacol.1999,51:1241-1250.
[4]Leppert PS,Fix JA.Use of everted intestinal rings for in vitro examination of oral absorption potential[J].J Pharm Sci.1994,83:976-981.
[5]Comaire G,Woodley JF,Saivin S,et al.Effect of polyoxyl 35 castor oil and polysorbate 80 on the intestinal absorption of digoxin in vitro[J].Arzneimittelforsch.2000,50:576-579.
[6]Brown JR,Collett JH,Attwood D,et al.Influence of monocaprin on the permeability of a diacidic drug BTA-243 across Caco-2 cell monolayers and everted gut scas[J].Int J Pharm.2002,245:133-142.
[7]Xianyi S,Xiaoling F.Transport characteristics of 9-nitrocamptothecin in the human intestinal cell line Caco-2 and everted gut sacs[J].Int J Pharm.2004,272:161-171.
[8]梁桂贤,刘谦民.药物肠吸收研究方法近况[J].国外医药-合成药-生化药-制剂分册,1998,19(4):251-252.
[9]Allen RH,Robert AC,Philip SB.Caco-2 cell monolayers as a model for drug transport across the intestinal mucosa[J].Pharm Res.1990,7(9):902-910.
[10]Hidalgo IJ,Raub TJ,Borchardt RT.Characterization of the human colon carcinoma cell line(Caco-2)as a model system for intestinal epithelial permeability[J].Gastroenterology.1989,96:736-749.
[11]Artursson P,Palm K,Luthman K.Caco-2 monolayers in experimental and theoretical predictions of drug transport[J].Adv Drug Deliv Rev.2001,46(1-3):27-43.
[12]Hochman JH,Yamazaki M,Ohe T,et al.Evaluation of drug interactions with P-glycoprotein in drug discovery:in vitro assessment of the potential for drug-drug interactions with P-glycoprotein[J].Curr Drug Metab.2002,3(3):257-273.
[13]Braun A,Hammerle S,Suda K,et al.Cell cultures as tools in biopharmacy[J].Eur J Pharm Sci.2000,11(Suppl 2):S51-S60.
[14]Lennermas H,Ahrenstedt O,Hallgren R,et al.Reginal jejunal perfusion,a new in vivo approach to study oral drug absorption in man[J].Pharm Res.1992,9:1243-1251.
[15]陈军辉,陈俊.苯丙醇胺肠吸收特性的研究[J].中国医院药学杂志,2002,20(2):73-75.
[16]Eva MS,Kara JC,Regina L,et al.Uptake and metabolism of Sphingolipids in isolated intestinal loops of mice[J].J Nutr.1994,124(5):702-712.
[17]Lennernas H,Palm K,Fagerholm U,et al.Comparison between active and passive drug transport in human intestinal epithelial(Caco-2) cells in vitro and human jejunum in vivo[J].Int J Pharm.1996,127(1):103-107.
[18]WilSon FA,Dietschy IM.The intestinal unstirred water layer:its surface area and effect on active transport kinetics[J].Biochim Biophys Acta.1974,363(1):112-126.
[19]Artursson P,Ungell AL,Lofroth JE.Selective paracellualr permeability in two models of intestinal absorption:cultured monolayers of human intestinal epithelial cells and rat intestinal segments[J].Pharrn Res.1993,10(8):1123-1129.
[20]LennernasH,Nilsson D,Aquilonius SM,et al.The effect of L-leucin on the absorption of levodopa,studied by regional jejeunal perfusion in man[J].Br J Clin Pharmacol.1993,35(3):243-250.
[21]Hidalgo IJ,Borchardt RT.Transport of a large neutral amino acid(phenylalanine)in a human intestinal epithelial cell line:Caco-2[J].Biochim Biophys Acta.1990,1028(1):25-30.
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