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

异喹胍的4-羟化在人体内是多态性的。比较了奎尼丁和奎宁在大鼠和人肝微粒体中抑制异喹胍4-羟化酶的动力学。奎尼丁是人肝异喹胍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要低60倍。在大鼠肝微粒体中，奎宁的抑制作用比奎尼丁强约50倍。这两种化合物都能够抑制大鼠和人体中>95%的4-羟化酶活性。奎尼丁和奎宁都是大鼠和人类中的碎屑素4-羟化酶活性的竞争性抑制剂，它们的效力是相反的。这表明细胞色素P-450 dbl的活性位点的性质在两个物种之间不同。本文研究了硫氮卓酮对大鼠肝脏混合功能单加氧酶系统的影响。曲美双酮代谢和4-羟基安替比林尿排泄增加，但异喹胍4-羟基化 ...更多信息 被地尔硫卓抑制了在人体研究中，安替比林清除率降低，尤其是4-羟基安替比林的形成清除率降低。地尔硫卓抑制异喹胍4-羟基化，不改变曲美双酮代谢。从这个结果来看，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，对异喹胍4-羟基化的抑制作用在大鼠和人中均被显示。本文研究了依诺沙星对大鼠和人肝微粒体药物代谢酶的影响。依诺沙星可降低人茶碱的血浆清除率，大鼠多次给药可降低3-羟甲基安替比林的形成清除率，而增加去甲安替比林的形成清除率。依诺沙星对曲美双酮代谢无影响。在人体中，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著降低。依诺沙星可促进三甲双酮代谢。结果提示，依诺沙星对多种P-450同工酶有不同程度的抑制和诱导作用，安替比林和三甲双酮参与的P-450同工酶在大鼠和人之间可能存在差异，提示将大鼠肝脏药物代谢酶活性数据外推至人时应特别谨慎，并应使用多种模型底物。少

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