Li Xue-Qing, Björkman Anders, Andersson Tommy B, Gustafsson Lars L, Masimirembwa Collen M
Department of Drug Metabolism and Pharmacokinetics and Bioanalytical Chemistry, AstraZeneca R and D Mölndal, 431 83 Mölndal, Sweden.
Eur J Clin Pharmacol. 2003 Sep;59(5-6):429-42. doi: 10.1007/s00228-003-0636-9. Epub 2003 Aug 12.
Knowledge about the metabolism of anti-parasitic drugs (APDs) will be helpful in ongoing efforts to optimise dosage recommendations in clinical practise. This study was performed to further identify the cytochrome P(450) (CYP) enzymes that metabolise major APDs and evaluate the possibility of predicting in vivo drug clearances from in vitro data.
In vitro systems, rat and human liver microsomes (RLM, HLM) and recombinant cytochrome P(450) (rCYP), were used to determine the intrinsic clearance (CL(int)) and identify responsible CYPs and their relative contribution in the metabolism of 15 commonly used APDs.
CL(int) determined in RLM and HLM showed low (r(2)=0.50) but significant ( P<0.01) correlation. The CL(int) values were scaled to predict in vivo hepatic clearance (CL(H)) using the 'venous equilibrium model'. The number of compounds with in vivo human CL data after intravenous administration was low ( n=8), and the range of CL values covered by these compounds was not appropriate for a reasonable quantitative in vitro-in vivo correlation analysis. Using the CL(H) predicted from the in vitro data, the compounds could be classified into three different categories: high-clearance drugs (>70% liver blood flow; amodiaquine, praziquantel, albendazole, thiabendazole), low-clearance drugs (<30% liver blood flow; chloroquine, dapsone, diethylcarbamazine, pentamidine, primaquine, pyrantel, pyrimethamine, tinidazole) and intermediate clearance drugs (artemisinin, artesunate, quinine). With the exception of artemisinin, which is a high clearance drug in vivo, all other compounds were classified using in vitro data in agreement with in vivo observations. We identified hepatic CYP enzymes responsible for metabolism of some compounds (praziquantel-1A2, 2C19, 3A4; primaquine-1A2, 3A4; chloroquine-2C8, 2D6, 3A4; artesunate-2A6; pyrantel-2D6). For the other compounds, we confirmed the role of previously reported CYPs for their metabolism and identified other CYPs involved which had not been reported before.
Our results show that it is possible to make in vitro-in vivo predictions of high, intermediate and low CL(int) drug categories. The identified CYPs for some of the drugs provide a basis for how these drugs are expected to behave pharmacokinetically and help in predicting drug-drug interactions in vivo.
了解抗寄生虫药物（APDs）的代谢情况将有助于在临床实践中不断优化剂量推荐。本研究旨在进一步确定代谢主要APDs的细胞色素P(450)（CYP）酶，并评估根据体外数据预测体内药物清除率的可能性。
使用体外系统、大鼠和人肝微粒体（RLM、HLM）以及重组细胞色素P(450)（rCYP）来测定内在清除率（CL(int)），并确定负责代谢15种常用APDs的CYP及其相对贡献。
在RLM和HLM中测定的CL(int)显示出低（r(2)=0.50）但显著（P<0.01）的相关性。使用“静脉平衡模型”将CL(int)值进行缩放以预测体内肝脏清除率（CL(H)）。静脉给药后有体内人CL数据的化合物数量较少（n=8），且这些化合物的CL值范围不适用于合理的体外-体内定量相关性分析。根据体外数据预测的CL(H)，这些化合物可分为三类：高清除率药物（>70%肝血流量；阿莫地喹、吡喹酮、阿苯达唑、噻苯达唑）、低清除率药物（<30%肝血流量；氯喹、氨苯砜、乙胺嗪、喷他脒、伯氨喹、噻嘧啶、乙胺嘧啶、替硝唑）和中等清除率药物（青蒿素、青蒿琥酯、奎宁）。除青蒿素在体内是高清除率药物外，所有其他化合物根据体外数据分类与体内观察结果一致。我们确定了负责某些化合物代谢的肝脏CYP酶（吡喹酮 - 1A2、2C19、3A4；伯氨喹 - 1A2、3A4；氯喹 - 2C8、2D6、3A4；青蒿琥酯 - 2A6；噻嘧啶 - 2D6）。对于其他化合物，我们证实了先前报道的CYPs在其代谢中的作用，并确定了其他以前未报道过的参与代谢的CYPs。
我们的结果表明，有可能对高、中、低CL(int)药物类别进行体外-体内预测。确定的某些药物的CYPs为这些药物的药代动力学行为提供了依据，并有助于预测体内药物-药物相互作用。
