Polymorphism of Hepatic Dung Metabolizing Enzymes and Extrapolation of its Data from Animal to Human

肝粪代谢酶的多态性及其数据从动物到人类的外推

• 批准号: 01570114
• 负责人: YASUHARA Hajime
• 金额: $ 1.34万
• 依托单位: Showa University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1989
• 资助国家: 日本
• 起止时间: 1989 至 1990
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-01570114/
• 关键词: drug metabolizing enzymes; polymorphism; model substrates; antipyrine; trimethadione; debrisoquine; extrapolation; エノキサシン; チトクロ-ムPー450; ラット

The 4-hydroxylation of debrisoquine is polymorphic in man. The kinetics of inhibition of debrisoquine 4-hydroxylase activity by quinidine and quinine in rat and human liver microsomes have been compared. Quinidine is a potent inhibitor of debrisoquine 4-hydroxylase activity of human liver. However, its stereoisomer, quinine is some 60 times less potent. In the rat liver microsomes quinine is approximately 50 times more potent an inhibitor than quinidine. Both compounds are able to inhibit >95% of 4-hydroxylase activity in both rat and human. Both quinidine and quinine are competitive inhibitor of debrisouine 4-hydroxylase activity in rat and man, their potency is reversed. This suggests that the nature of the active site of cytochrome P-450dbl differ between the two species. The effects of dilitiazem on hepatic mixed function-monoxygenase system was investigated in rat. Trimethadione metabolism and urinary excretion of 4-hydroxyantipyrine were increased but debrisoquine 4-hydroxylation … More was inhibited by diltiazem. In human study, antipyrine clearance was decreased, especially formation clearance of 4-hydroxyantipyrine was decreased. Debrisoquine 4-hydroxylation was inhibited and trimethadione metabolism was not changed by diltiazem. From this results, the effects of diltiazem on 4-hydroxylation of antipyrine was reversed in rat and human, however, inhibitory effect of 4-hydroxylation of debrisoquine was shown in both rat and human. The effects of enoxacin on hepatic microsomal drug metabolizing enzymes were studied in rat and man, because enoxacin decresed plasma clearance of theophyllin in man. Formation clearance of 3-hydroxymethylantipyrine was decreased, while that of norantipyrine was increased by multiple dose of enoxacin in rat. Enoxacin had no effect on trimethadione metabolism in rat. In man, clearances of 3-hydroxymethylantipyrine, norantipyrine and 4-hydroxyantipyrine were all significantly decreased after treatment of enoxacin. Trimethadione metabolism was enhanced by enoxacin. This results suggest that enoxacin affects several P-450 isozymes in different manner such as inhibition and induction and that characteristics of P-450 isozymes involved in antipyrine and trimethadione are possibly different between rat and man. From these studies, it may indicate that the data on hepatic drug metabolizing enzyme capacity in rat should be extrapolated to man with extreme caution and with using many model substrates. Less

异喹啉的 4-羟基化在人体中具有多态性。比较了奎尼丁和奎宁在大鼠和人肝微粒体中抑制异喹啉 4-羟化酶活性的动力学。奎尼丁是人肝脏异喹啉 4-羟化酶活性的有效抑制剂。然而，其立体异构体奎宁的效力大约低 60 倍。在大鼠肝微粒体中，奎宁的抑制剂效力比奎尼丁强大约 50 倍。两种化合物都能抑制大鼠和人类 95% 以上的 4-羟化酶活性。奎尼丁和奎宁都是大鼠和人体内碎片木因 4-羟化酶活性的竞争性抑制剂，其效力相反。这表明这两个物种的细胞色素 P-450dbl 活性位点的性质不同。研究了地利硫卓对大鼠肝脏混合功能-单加氧酶系统的影响。地尔硫卓可抑制三甲二酮代谢和 4-羟基安替比林的尿排泄，但异喹啉 4-羟基化作用受到抑制。在人体研究中，安替比林的清除率降低，尤其是4-羟基安替比林的形成清除率降低。地尔硫卓可抑制地尔异喹 4-羟基化，且不改变三甲二酮代谢。从该结果来看，地尔硫卓对安替比林4-羟基化的作用在大鼠和人中被逆转，然而，在大鼠和人中均显示出异喹啉4-羟基化的抑制作用。在大鼠和人类中研究了依诺沙星对肝微粒体药物代谢酶的影响，因为依诺沙星降低了人类茶碱的血浆清除率。多剂量依诺沙星在大鼠体内使3-羟甲基安替比林的形成清除率降低，而去甲安替比林的形成清除率增加。依诺沙星对大鼠三甲二酮代谢无影响。在人类中，依诺沙星治疗后，3-羟甲基安替比林、去甲安替比林和4-羟基安替比林的清除率均显着降低。依诺沙星可增强三甲二酮代谢。该结果表明，依诺沙星以不同的方式（例如抑制和诱导）影响几种P-450同工酶，并且涉及安替比林和三甲二酮的P-450同工酶的特征在大鼠和人之间可能不同。从这些研究中，可能表明大鼠肝脏药物代谢酶能力的数据应该非常谨慎地外推到人类并使用许多模型底物。较少的

项目成果

S.Iida: "Effect of enoxacin on hepatic drug metabolizing enzymes:Comparison between rat and man." Asia Pacific Journal of Pharmacology. (1991)

S.Iida：“依诺沙星对肝脏药物代谢酶的影响：大鼠和人之间的比较。”

E. Uchida, et al: "The effect of diltiazem and verapamil on hepatic microsomal drug metabolizing enzymes in rat." The Showa Univ. J. Medical Sciences. 3. (1991)

E. Uchida 等人：“地尔硫卓和维拉帕米对大鼠肝微粒体药物代谢酶的影响”。

H.Sakai: "The effets of diltiazem on hepatic drug metabolizing enzymes in human using antipyrine,trimethadione and debrisoguine as model substrates" British Journal of Clinical Pharmacology. (1991)

H.Sakai：“地尔硫卓对人体肝脏药物代谢酶的影响，使用安替比林、三甲二酮和碎片喹啉作为模型底物”《英国临床药理学杂志》。

S. Kobayashi, et al.: "The specificity of inhibition of debrisoquine 4-hydroxylase activity by quinidine and quinine in the rat is the inverse of that in man." Biochem Pharmacol. 38. 2795-2799 (1989)

S. Kobayashi 等人：“奎尼丁和奎宁在大鼠中抑制异喹啉 4-羟化酶活性的特异性与在人类中的相反。”

E.Uchida: "The effect of diltiazen and verapamil on hepetic microsomal drug metabolizing enzymes in rat." The Showa University Jounal of Medical Sciences. 3. (1991)

E.Uchida：“地尔硫嗪和维拉帕米对大鼠肝微粒体药物代谢酶的影响。”