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

碎片喹的4-羟基化在人体内是多态的。比较了奎尼丁和奎宁对大鼠和人肝微粒体中碎片喹4-羟化酶活性的抑制动力学。奎尼丁是一种有效的肝脏碎片喹4-羟化酶活性抑制剂。然而，它的立体异构体奎宁的效力是它的60倍。在大鼠肝微粒体中，奎宁的抑制作用大约是奎尼丁的50倍。这两种化合物都能抑制大鼠和人体内95%的4-羟化酶活性。奎尼丁和奎宁在大鼠和人体内都是竞争性的德布嘧啶4-羟化酶活性抑制剂，它们的效力是相反的。这表明细胞色素P-450dbl活性位点的性质在两个物种之间有所不同。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。甲美二酮代谢和4-羟基安替吡林尿排泄增加，而地尔硫卓抑制碎片喹4-羟基化。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。地尔硫卓抑制了碎屑喹4-羟基化作用，不影响甲美二酮的代谢。由此可见，地尔硫卓对安替比林4-羟基化的影响在大鼠和人体内是逆转的，而对德比喹4-羟基化的抑制作用在大鼠和人体内都是存在的。研究了依诺沙星对大鼠和人肝微粒体药物代谢酶的影响，因为依诺沙星降低了人血浆中茶碱的清除率。多次给药可降低3-羟甲基安替比林的造形清除率，而提高诺替比林的造形清除率。依诺沙星对大鼠甲美二酮代谢无影响。在男性中，3-羟甲基安替比林、去甲安替比林和4-羟安替比林的清除率在依诺沙星治疗后均显著降低。依诺沙星可促进甲美沙酮代谢。结果表明，依诺沙星对几种P-450同工酶的影响方式不同，如抑制和诱导，而安替比林和甲美二酮所涉及的P-450同工酶的特征可能在大鼠和人之间有所不同。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非常谨慎地外推到人类，并使用许多模型底物。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