二氢吡啶类钙拮抗剂结构与药物动力学的定量关系分析

中国临床药理学与治疗学 ›› 2004, Vol. 9 ›› Issue (8): 868-871.

二氢吡啶类钙拮抗剂结构与药物动力学的定量关系分析

刘有平^{1, 2}, 宋乃宁^{1, 3}, 刘昌孝¹

¹天津药物研究院药代动力学和药效动力学国家重点实验室, 天津300193;
²沈阳药科大学药物代谢和药物动力学实验室, 沈阳110016, 辽宁;
³天津医科大学药理教研室, 天津300070

收稿日期:2004-04-16 修回日期:2004-06-30 出版日期:2004-08-26 发布日期:2020-11-20
通讯作者: 刘昌孝,男,院士,研究方向:药代动力学研究。Tel:022-23006863Fax:022-23006860 E-mail:liuchangxiao@163.com
基金资助:
国家“863”计划基金项目(№2003AA2Z347D)

Study on quantitative structures-pharmacokinetic relationship of dipyridines calcium ion antagonists

LIU You-Ping^{1, 2}, SONG Nai-Ning^{1, 3}, LIU Chang-Xiao¹

¹National Key Laboratory of Pharmacokinetics and Pharmacodynamics, Tianjin Institute of Pharmaceutical Research,Tianjin 300193, China;
²Laboratory of Drug Metablism and Pharmacokinetics, Shenyang Pharmaceutical University,Shenyang 110016, Liaoning, China;
³Department of Pharmacology, Tianjin Medical University, Tianjin 300070, China

Received:2004-04-16 Revised:2004-06-30 Online:2004-08-26 Published:2020-11-20

摘要/Abstract

摘要： 目的: 研究二氢吡啶类钙拮抗剂的化学结构与药物动力学的关系,为新药设计中早期筛选提供理论方法。方法: 采用Insight Ⅱ软件的分子力学和分子动力学程序首先将钙拮抗剂的结构式转化为三维结构,并进行能量优化,使得结构趋于合理。HyperChem软件计算优化好的结构的理化性质参数(Log P,Surface Area,Volume,Hydration Energy,Refractivity,Polarizability)。对钙拮抗剂药物的理化参数与其药物动力学参数之间关系进行统计分析研究。结果: 钙拮抗剂的疏水性常数(Log P)值与血管外给药后的达峰时间(T_max)存在二次方程关系,二者的相关性达到0.9 以上。结论: 二氢吡啶类钙拮抗剂药物的疏水性常数(Log P)值与给药后的达峰时间(T_max)存在的关系对该类药物的进一步结构改造,设计新药具有重要的指导意义。

关键词: 二氢吡啶类化合物, 钙拮抗剂, 分子力学和分子动力学, 药代动力学参数

Abstract: AIM: To study on the quantitative structures-pharmacokinetic relationship of dipyridines calcium ion antagonists to provide the theoretic method to screen new drugs in early period.METHODS: The structures of calcium ion antagonists were conversed from two to three dimensional structure by Insight Ⅱ Program. The conversed structures were optimized to the minimum energy by the steepest descent and conjugate gradient methods. The physico-chemical parameters of the optimized structures, including Log P, surface area, volume, hydration energy, refractivity and polarizability, were calculated by HyperChem Program.The interrelation between structures and pharmacokinetic parameters for calcium ionantagonists was analyzed.RESULTS: There was a good correlation between the hydrophobicity constants (Log P) and the reached peak time (Tmax) after extravenous administration of the calcium ion antagonists to the subjects. The correlation coefficient was over 0.9.CONCLUSION: The correlation between the chemical structure and its pharmacokinetic parameters can provide instructions to new drug design for calcium ion antagonists.

Key words: dipyridines, calcium ion antagonists, molecular mechanics and dynamics, pharmacokinetic parameters

中图分类号:

R969.1

刘有平, 宋乃宁, 刘昌孝. 二氢吡啶类钙拮抗剂结构与药物动力学的定量关系分析[J]. 中国临床药理学与治疗学, 2004, 9(8): 868-871.

LIU You-Ping, SONG Nai-Ning, LIU Chang-Xiao. Study on quantitative structures-pharmacokinetic relationship of dipyridines calcium ion antagonists[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2004, 9(8): 868-871.

参考文献

1 Ghafourian T, Barzegar-Jalali M, Hakimiha N, Cronin MT. Quantitative structure-pharmacokinetic relationship modelling : Apparent volume of distribution[J].J Pharm Pharmacol, 2004;56(3):339-50
2 Turner JV, Maddalena DJ, Agatonovic-Kustrin S. Bioavailability prediction based on molecular structure for a diverse series of drugs[J].Pharm Res, 2004;21(1):68-82
3 Turner JV, Maddalena DJ, Cutler DJ.Pharmacokinetic parameter prediction from drug structure using artificial neural networks[J].Int J Pharm, 2004;270(2):209-19
4 Regardh C G, Edgar B, Olsson R, Kendall M, Collste P, Shansky C.Pharmacokinetics of felodipine in patients with liver disease[J].Eur J Clin Pharmacol, 1989;36(5):473-9
5 Fujimura A, Ohashi K, Sugimoto K, Kumagai Y, Ebihara A. Chronopharmacological study of nitrendipine in healthy subjects[J].J Clin Pharmacol, 1989;29(10):909-15
6 Guerret M, Cheymol G, Hubert M, Julien-Larose C, Lavene D.Simultaneous study of the pharmacokinetics of intravenous and oral nicardipine using a stable isotope[J].Eur J Clin Pharmacol, 1989;37(4):381-5
7 Chen DG, Feng QP, Wang ZQ, Chen K.Pharmacodynamics and pharmacokinetics of nifedipine in patients with congestive heart failure[J].Acta Pharmacol Sin, 1989;10(3):233-8
8 Pasanisi F, Meredith PA, Reid JL.The pharmacodynamics and pharmacokinetics of a new calcium antagonist nisoldipine in normotensive and hypertensive subjects[J].Eur J Clin Pharmacol, 1985;29(1):21-4
9 Shenfield GM, Boutagy J, Stokes GS, Rumble F, Dunagan F. The pharmokinetics of isradipine in hypertensive subjects[J]. Eur J Clin Pharmacol, 1990;38(2):209-11
10 Boelaert J, Valcke Y, Dammekens H, De Vriese G, Ahr G, SchurgersM, et al.Pharmacokinetics of nisoldipine in renal dysfunction[J].Eur J Clin Pharmacol, 1988;34(2):207-9
11 Kobayashi H, Kobayashi S, Dalrymple PD, Wood SG, Chasseaud LF.Absorption, metabolism and excretion after oral administration of a new Ca antagonist, 14C-benidipine hydrochloride to man[J].Xenobiotica, 1997;27(6):597-608
12 Inoue Y, Nakayama K, Wachi M, Kumakura K, Matsumoto T, Iwamoto M, et al.Absorption, distribution, metabolism and excretion of 2, 6-dimethyl-3, 5-dimethoxycarbony l-4-(o-difluoromethoxyphenyl)-1, 4-dihydropyridine (PP-1466) in rat[J].Arzneimittelforschung, 1985;35(5):813-8
13 Sannita WG, Busico S, Di Bon G, Ferrari A, Riela S.Pharmacokinetics and electro-encephalographic effects of darodipine 50-200 mg modified release (MR) acute oral administration: dose-finding study in healthy volunteers[J].Int J Clin Pharmacol Res, 1993;13(5):281-91
14 Rosillon D, Stockis A, Poli G, Acerbi D, Lins R, Jeanbaptiste B.Food effect on the oral bioavailability of manidipine : single dose, randomized, crossover study in healthy male subjects[J].Eur J Drug Metab Pharmacokinet, 1998;23(2):197-202
15 Seydel JK, Schaper KJ.Quantitative structure-pharmacokineticrelationships and drug design[J].Opharmacol Ther, 1982;15(2):131-82
16 Fleisher D, Li C, Zhou Y, Pao LH, Karim A.Drug, meal and formulation interactions influencing drug absorption after oral administration[J].Clin Pharmacokinet, 1999;36(3):233-54

[1]	祝建平, 孙建国, 彭英, 王广基. 人体关键药代动力学参数预测方法[J]. 中国临床药理学与治疗学, 2011, 16(6): 699-709.
[2]	李家富, 章茂顺, 王家良, 符宗胤. 醋柳黄酮对血管平滑肌细胞胞内游离钙浓度的影响[J]. 中国临床药理学与治疗学, 2004, 9(3): 305-307.