有限采样法评价肝脏CYP3A 代谢活性的实验研究

中国临床药理学与治疗学 ›› 2008, Vol. 13 ›› Issue (12): 1404-1410.

有限采样法评价肝脏CYP3A 代谢活性的实验研究

朱学慧^1,2, 娄建石², 焦建杰², 张才丽², 刘昌孝³

¹天津医科大学药学院临床药学教研室,²基础医学院药理教研室, 天津 300070;
³天津市药物研究院药动学和药效学国家重点实验室, 天津 300193

收稿日期:2008-07-07 修回日期:2008-11-29 发布日期:2020-10-30
通讯作者: 娄建石,男,教授,博士生导师,研究方向:临床药理学。Tel:022-23542686E-mail:jianshilou@sina.com
作者简介:朱学慧,女,博士研究生,讲师,研究方向:临床药理学。Tel:022-23529457E-mial:zhuxuehui@tijmu.edu.cn
基金资助:
国家973计划资助项目(2004CB518902)

Experimental study on limited sampling strategy to predict metabolizing activity of hepatic CYP3A

ZHU Xue-hui^1,2, LOU Jian-shi¹, JIAO Jian-jie¹, ZHANG Cai-li¹, LIU Chang-xiao³

¹Pharmacology Department, Basic Medical College, Tianjin Medical University, ²Clincal Pharmacy Department, College of Pharmaceutical Science, Tianjin Medical University, Tianjin 300070, China;
³Tianjin State Key Laboratory of Pharmacokinetics and Pharmacodynamics, Tianjin Institute of Pharmaceutical Research, Tianjin 300193, China

Received:2008-07-07 Revised:2008-11-29 Published:2020-10-30

摘要/Abstract

摘要： 目的以细胞色素P450(CYP) 3A 探针药物咪哒唑仑(MDZ) 的系统清除率(Cls) 为指标, 评价有限采样法(LSS) 预测肝脏CYP3A 抑制状态下代谢活性的可行性。方法采用系列剂量的CYP3A选择性抑制剂酮康唑预处理大鼠, 静脉注射MDZ后在若干时间点收集血浆样品并检测MDZ 浓度,经逐步回归分析和Jack-knife 验证建立LSS 模型。对经相同处理的另一随机群体进行验证分析, 评价该LSS 模型方程的准确性和重现性。结果由两点(60 、90 min) 或三点(30 、60 、90 min 或30 、60 、120 min) 血浆药物浓度建立的LSS 预测模型所得到的Cls 估计值(Clest) 与实际计算值(Clobs) 之间具有良好的相关性, 误差小, 特别是两点LSS 模型则更为简便。结论本研究结果表明, 以MDZ Cls 为指标, 采用LSS 评价大鼠肝脏CYP3A 抑制状态下的代谢活性是一种准确而简便的方法, 为今后推广到临床评价肝脏代谢功能从而制定和调整治疗药物的给药方案提供了理论依据和实验室证据。

关键词: 有限采样法, 肝脏, CYP3A, 咪哒唑仑, 酮康唑

Abstract: AIM: To evaluate feasibility of a limited sampling strategy (LSS) in the prediction of inhibited hepatic CYP3A activity with systemic clearance of midazolam (MDZ), a phenotyping probe drug for hepatic CYP3A activity.METHODS: Linear regression analysis and a Jack-knife validation procedures were performed in one group of rats pretreated with a serial doses of ketoconazole, a selective inhibitor on CYP3A, as training set to establish the most informative LSS model for accurately estimating the clearance of MDZ. Another group of rats in same setting were used as validation set to estimate the individual clearance (Clest) based on predictive equations derived from the training set.RESULTS: LSS models derived from two or three sampling time points, including 60 and 90 min, 30, 60 and 90 min and 30, 60 and 120 min, exhibited best correlation and acceptable errors between Clobs and Clest were chosen to evaluate to hepatic CYP3A activity.CONCLUSION: The results indicated that limited plasma sampling for predicting systemic clearance of MDZ is a less complicated method to evaluation of CYP3A phenotyping when the activity of hepatic CYP3A was inhibited.The present study provided theoretical basis and laboratory evidence for LSS to clinically evaluate metabolizing function of liver and design rational drug regimen.

Key words: limited sampling strategy, hepatic, CYP3A, midazolam, ketoconazole

中图分类号:

R969

朱学慧, 娄建石, 焦建杰, 张才丽, 刘昌孝. 有限采样法评价肝脏CYP3A 代谢活性的实验研究[J]. 中国临床药理学与治疗学, 2008, 13(12): 1404-1410.

ZHU Xue-hui, LOU Jian-shi, JIAO Jian-jie, ZHANG Cai-li, LIU Chang-xiao. Experimental study on limited sampling strategy to predict metabolizing activity of hepatic CYP3A[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2008, 13(12): 1404-1410.

参考文献

[1] Chovan JP, Ring SC, Yu E, et al.Cytochrome P450 probe substrate metabolism kinetics in Sprague Dawley rats[J].Xenobiotica, 2007, 37(5):459-473.
[2] Liu YT, Hao HP, Liu CX, et al.Drugs as CYP3A probes, inducers, and inhibitors[J].Drug Metab Rev, 2007, 39(4):699-721.
[3] Emoto C, Yamato Y, Sato Y, et al.Non-invasive method to detect induction of CYP3A4 in chimeric mice with a humanized liver[J].Xenobiotica, 2008, 38(3):239-248.
[4] 朱学慧, 娄建石.CYP3A 选择性探针药物的评价[J].中国临床药理学与治疗学, 2004, 9(4):365-369.
[5] Thummel KE, Shen DD, Podoll TD, et al.Use of midazolam as a human cytochrome P450 3A probe: In vitro-in vivo correlations in liver transplant patients[J].J Pharmacol Exp Ther, 1994, 271(1):549-556.
[6] Kim JS, Nafziger AN, Tsunoda SM, et al.Limited sampling strategy to predict AUC of the CYP3A phenotyping probe midazolam in adults:application to various assay techniques[J].J Clin Pharmacol, 2002, 42(4):376-382.
[7] Wada K, Takada M, Kotake T, et al.Limited sampling strategy for mycophenolic acid in Japanese heart transplant recipients:comparison of cyclosporin and tacrolimus treatment[J].Circ J, 2007, 71(7):1022-1028.
[8] Wada K, Takada M, Ueda T, et al.Pharmacokinetic study and limited sampling strategy of cyclosporine in Japanese heart transplant recipients[J].Circ J, 2007, 70(10):1307-1311.
[9] 丁俊杰, 焦正, 李中东, 等.有限采样法估算口服环孢素微乳剂的生物等效性[J].中国药学杂志,2007, 42(4):283-288.
[10] Miura M, Satoh S, Niioka T, et al.Limited sampling strategy for simultaneous estimation of the area under the concentration-time curve of tacrolimus and mycophenolic acid in adult renal transplant recipients[J].Ther Drug Monit, 2008, 30(1):52-59.
[11] Hao C, Erzheng C, Anwei M, et al.Validation of limited sampling strategy for the estimation of mycophenolic acid exposure in Chinese adult liver transplant recipients[J]. Liver Transpl, 2007, 13(12):1684-1693.
[12] 高志伟, 施孝金, 余琛, 等.混合探针底物法同时预测细胞色素P450 酶5 种亚型的抑制作用[J].药学学报, 2007, 42(6):589-594.
[13] Matthew D, Brennan B, Zomorodi K, et al.Disposition of azole antifungal agents Ⅰ:Nonlinearities in ketoconazole clearance and binding in rat liver[J].Pharm Res, 1993, 10(3):418-422.
[14] Ervine CM, Matthew DE, Brennan B, et al.Comparison of ketoconazole and fluconazole as cytochrome P450 inhibitors: Use of steady-state infusion approach to achieve plasma concentration-response relationships [J].Drug Metab Dispo, 1996, 24(2):211-215.
[15] Zhu B, Ou-Yang DS, Cheng ZN, et al.Single plasma sampling to predict oral clearance of CYP3A probe midazolam[J].Acta Pharmacol Sin, 2001, 22(7):634-638.
[16] Ma JD, Nafziger AN, Kashuba ADM, et al.Limited sampling strategy of s-warfarin concentrations, but not warfarin S R ratios, accurately predicts S-warfarin AUC during baseline and inhibition in CYP2C9 extensive metabolizers [J].J Clin Pharmacol, 2004, 44(6):570-576.
[17] Suarez-Kurtz G, Ribeiro FM, Vicente FL, et al.Development and validation of limited-sampling strategies for predicting amoxicillin pharmacokinetic and pharmacodynamic parameters[J].Antimicrob Agents Chemother, 2001, 45(11):3029-3036.
[18] 郑姣, 周宏灏.黄酮类化合物对细胞色素P450CYP1, 2E1, 3A4 和19 的影响[J].药学学报, 2007,42(1):8-12.
[19] 朱冰, 陈国林, 陈小平, 等.中国汉族人群中CYP3AP1 基因型与CYP3A 活性的相关性研究(英文) [J].中国药理学报:英文版, 2002, 23(6):567-572.
[20] Uhing MR, Beno DWA, Jiyamapa-Serna VA, et al.The effect of anesthesia and surgery on CYP3A activity in rats [J].Drug Metab Dispos, 2004, 32(11):1325-1330.
[21] Lee LS, Bertino JS Jr, Nafziger AN.Limited sampling models for oral midazolam:midazolam plasma concentrations, not the ratio of 1-hydroxymidazolam to midazolam plasma concentrations, accurately predicts AUC as a biomarker of CYP3A activity[J].J Clin Pharmacol, 2006, 46(2):229-234.
[22] Shadle CR, Lee Y, Majumdar AK, et al.Evaluation of potential inductive effects of aprepitant on cytochrome P450 3A4 and 2C9 activity[J].J Clin Pharmacol, 2004, 44(3):215-223.
[23] Allonen H, Ziegler G, Klotz U.Midazolam kinetics[J]. Clin Pharmacol Ther, 1981, 30(5):653-661.
[24] Frye RF.Probing the world of cytochrome P450 enzymes [J].Mol Interv, 2004, 4(3):157-162.
[25] Chainuvati S, Nafziger AN, Leeder JS, et al.Combined phenotypic assessment of cytochrome p450 1A2, 2C9, 2C19, 2D6, and 3A, N-acetyltransferase-2, and xanthine oxidase activities with the “ Cooperstown 5 +1 cocktail” [J].Clin Pharmacol Ther, 2003, 74(5):437-447.
[26] Veronese ML, Gillen LP, Burke JP, et al.Exposure-dependent inhibition of intestinal and hepatic CYP3A4 in vivo by grapefruit juice[J].J Clin Pharmacol, 2003, 43(8):831-839.
[27] Gurley BJ, Gardner SF, Hubbard MA, et al.In vivo assessment of botanical supplementation on human cytochrome P450 phenotypes:Citrus aurantium, Echinacea purpurea, milk thistle, and saw palmetto[J].Clin Pharmacol Ther, 2004, 76(5):428-440.