厄贝沙坦与氢氯噻嗪联用在大鼠体内剂量优化的定量研究

中国临床药理学与治疗学 ›› 2012, Vol. 17 ›› Issue (5): 521-528.

厄贝沙坦与氢氯噻嗪联用在大鼠体内剂量优化的定量研究

黄晓晖¹, 王钦¹, 王鲲², 黄继汉², 裘福荣³, 唐海沁⁴, 李俊¹

¹安徽医科大学药学院,合肥 230032,安徽;
²上海中医药大学药物临床研究中心,上海 201203;
³上海中医药大学附属曙光医院药代动力学实验室,上海 201203;
⁴安徽医科大学第一附属医院心内科,合肥 230022,安徽

收稿日期:2012-03-12 修回日期:2012-04-12 出版日期:2012-05-26 发布日期:2012-05-28
通讯作者: 李俊,男,博士,教授,博士生导师,研究方向:临床药理学和抗炎免疫药理学。Tel: 0551-5061001 E-mail: lijun@ahmu.edu.cn
作者简介:黄晓晖,男,博士,副教授,硕士生导师,研究方向:定量药理学和临床药代动力学。Tel: 13855183138 E-mail: mathdrug@sina.com
基金资助:
国家自然科学基金(81173133);安徽省优秀青年科技基金(08040106813);上海市教委创新项目 (10YZ61)

Drug-drug interaction between irbesartan and hydrochlorothiazide in renal hypertensive rats: A case study of dose optimization

HUANG Xiao-hui¹, WANG Qin¹, WANG Kun², HUANG Ji-han², QIU Fu-rong³, TANG Hai-qin⁴, LI Jun¹

¹School of Pharmacy, Anhui Medical University, Hefei 230032, Anhui, China;
²Center of Drug Clinical Research, Shanghai University of Chinese Medicine, Shanghai 201203, China;
³Pharmacokinetics Laboratory, Shuguang Hospital Attached with Shanghai Chinese Medicine University, Shanghai 201203, China;
⁴Department of Cardiology, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui , China

Received:2012-03-12 Revised:2012-04-12 Online:2012-05-26 Published:2012-05-28

摘要/Abstract

摘要： 目的:应用权重配方法及非线性混合效应模型,对厄贝沙坦和氢氯噻嗪在肾性高血压大鼠体内联用的剂量优化进行定量评价。方法: 根据权重配方设计,将肾性高血压大鼠分为厄贝沙坦和氢氯噻嗪不同剂量组合的6个用药组,以收缩压和舒张压的变化率作为药效指标。综合建立和应用权重配方模型及非线性混合效应模型分析降压效应,评价两药联用在大鼠体内的降压及交互作用,分析最佳剂量配比,并做确定性实验。对权重配方原法和权重配方群体法的计算结果进行比较。结果: 成功建立权重配方模型及其群体模型,联用中组分重要程度为厄贝沙坦大于氢氯噻嗪,厄贝沙坦与氢氯噻嗪存在协同作用,在大鼠体内的最优剂量配比为厄贝沙坦∶氢氯噻嗪=10∶1。权重配方原法和群体法在评价组分重要程度、理论优化组方及剂量优化比例等方面的结论相同,但群体法由于采用个体效应值直接计算,对权重指数等参数的计算更为精确,并提供个体间及个体内变异等信息。结论:综合应用权重配方法及非线性混合效应模型,可定量评价厄贝沙坦和氢氯噻嗪联用在大鼠体内的药物相互作用规律,并提供最佳剂量配比的信息,为临床合理药物联用提供依据。

关键词: 厄贝沙坦, 氢氯噻嗪, 权重配方法, 非线性混合效应模型, 剂量优化

Abstract: AIM: To quantitatively study the dose optimization of drug-drug interaction of irbesartan and hydrochlorothiazide in renal hypertensive rats using weighted modification model and nonlinear mixed effect model.METHODS: Renal hypertensive rats were randomly divided into six groups with different dose combination according to the experimental design of weighted modification method. The rates of change of systolic and diastolic blood pressures were measured as pharmacodynamic indices. Original and population weighted modification methods were comprehensively used to analyze the experimental data and evaluate the drug-drug interaction and dose optimization of irbesartan/hydrochlorothiazide in rats. The results and characteristics of original and population weighted modification methods were compared.RESULTS:The weighted modification models were built successfully. The optimal combination proportion between these two drugs was 10∶1 (irbesartan/hydrochlorothiazide) and the nature of interaction was synergism. The role of irbesartan is more important than that of hydrochlorothiazide when used combinedly. The basic research conclusions of original and population weighted modification methods were the same. However, population weighted modification method can provide more accurate parameters such as weighted index and useful information of inter- and intra-individual variabilities.CONCLUSION: The weighted modification methods can be used to quantitatively evaluate the drug-drug interaction and dose optimization of irbesartan/hydrochlorothiazide in rats.

Key words: Irbesartan, Hydrochlorothiazide, Weighted modification method, Nonlinear mixed effect model, Dose optimization

中图分类号:

R544.1

黄晓晖, 王钦, 王鲲, 黄继汉, 裘福荣, 唐海沁, 李俊. 厄贝沙坦与氢氯噻嗪联用在大鼠体内剂量优化的定量研究[J]. 中国临床药理学与治疗学, 2012, 17(5): 521-528.

HUANG Xiao-hui, WANG Qin, WANG Kun, HUANG Ji-han, QIU Fu-rong, TANG Hai-qin, LI Jun. Drug-drug interaction between irbesartan and hydrochlorothiazide in renal hypertensive rats: A case study of dose optimization[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2012, 17(5): 521-528.

参考文献

[1] Tutunji LF, Tutunji MF, Alzoubi MI, et al. Simultaneous determination of irbesartan and hydrochlorothiazide in human plasma using HPLC coupled with tandem mass spectrometry: Application to bioequivalence studies[J]. J Pharm Biomed Anal, 2010, 51(4):985-990.
[2] Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of high blood pressure: the JNC 7 report[J]. JAMA, 2003, 289(19):2560-2572.
[3] European society of hypertension-european society of Cardiology Guidelines Committee. 2003 European Society of Hypertension-European Society of Cardiology guidelines for the management of arterial hypertension[J]. J Hypettens, 2003, 21(6): 1011-1053.
[4] 刘力生,龚兰生,孔灵芝,等.中国高血压防治指南(2005年修订版)[M]. 北京: 人民卫生出版社, 2005:24-35.
[5] Mao GG, Chen B, Sun H, et al. Relative bioavailability of irbesartan capsules in healthy volunteers[J]. Chin J Clin Pharmacol,2001, 17:207-209.
[6] Lapuerta P, Franklin S. The risks and benefits of initial irbesartan/hydrochlorothiazide combination therapy in patients with severe hypertension[J]. J Clin Hypertens, 2009, 11(5):277-283.
[7] Johan Gabrielsson, Dan Weiner. Pharmacokinetic and Pharmacodynamic Data Analysis: Concepts and Applications[M]. 2006.
[8] 谢海棠, 黄晓晖, 史军,主编. 定量药理与新药评价[M]. 人民军医出版社, 2011.
[9] 郑青山, 孙瑞元. 药物相互作用动力学分析方法及其CoDrug软件[J]. 中国临床药理学与治疗学, 2002, 7(1): 81-85.
[10] Zheng QS, Sun RY. Quantitative analysis of drug compatibility by weighed modification method[J]. Acta Pharmacol Sin, 1999, 20(11): 1043-1051.
[11] 黄继汉, 张密, 王民, 郑青山. 权重配方模型的非线性混合效应分析:一个药物相互作用研究实例[J]. 中国临床药理学与治疗学,2011, 16 (10): 1121-1125.
[12] Girerd X, Rosenbaum D, Aoun J. Efficacy and safety of early versus late titration of fixed-dose irbesartan/hydrochlorothiazide: ACTUAL study[J]. Blood Press, 2011, 20(S2):22-29.
[13] Vitale C, Marazzi G, Iellamo F, et al. Effects of nebivolol or irbesartan in combination with hydrochlorothiazide on vascular functions in newly-diagnosed hypertensive patients: The NINFE (Nebivololo, Irbesartan Nella Funzione Endoteliale) study[J]. Int J Cardiol, 2012,155(2):279-284.
[14] 李超,蒋勇,韦玉华.厄贝沙坦联合氢氯噻嗪治疗老年原发性高血压病的临床观察[J] , 柳州医学, 2011,24(3):135-137.
[15] Neutel JM. A comparison of the efficacy and safety of irbesartan/hydrochlorothiazide combination therapy with irbesartan monotherapy in the treatment of moderate or severe hypertension in diabetic and obese hypertensive patients: a post-hoc analysis review[J]. Postgrad Med, 2011,123(4):126-134.
[16] Greathouse M. A review of olmesartan medoxomil monotherapy: antihypertensive efficacy similar to that of other angiotensin II receptor blocker/hydrochlorothiazide combinations[J] ? Congest Heart Fail,2002, 8:313-320.
[17] Rane VP, Patil KR, Sangshetti JN, et al. Stability indicating LC method for simultaneous determination of irbesartan and hydrochlorothiazide in pharmaceutical preparations[J]. J Chromatogr Sci, 2010, 48(7):595-600.
[18] Maniadakis N, Ekman M, Fragoulakis V, et al. Economic evaluation of irbesartan in combination with hydrochlorothiazide in the treatment of hypertension in Greece[J]. Eur J Health Econ, 2011, 12(3):253-261.
[19] Derosa G, Ferrari I, Cicero AF. Irbesartan and hydrochlorothiazide association in the treatment of hypertension[J]. Curr Vasc Pharmacol, 2009, 7(2):120-136.
[20] Huang XH, Qiu FR, Xie HT, et al. Pharmacokinetic and pharmacodynamic interaction between irbesartan and hydrochlorothiazide in renal hypertensive dogs[J]. J Cardiovasc Pharmacol, 2005, 46(6):863-869.
[21] 黄晓晖, 裘福荣, 李俊. 厄贝沙坦在健康志愿者体内的药代动力学-药效学结合模型[J]. 中国药理学通报, 2005, 21(6): 712-715.
[22] Zheng QS, Wang XW, Gui CQ, et al. Quantitative design of optimal analgesic combination of acetaminophen, caffeine, and butalbital[J]. Acta Pharmacol Sin, 2001,22(8):691-696.
[23] Zheng QS, Gui CQ, Sun RY. A method of comprehensive evaluation of multiple response variables in drug interaction[J]. Indian J Pharmacol ,2001,33: 445-451.