Vandamme N, Broly F, Libersa C, Courseau C, Lhermitte M
Secteur Toxicologie du Laboratoire de Biochimie, Hôpital Calmette, CHRU de Lille, France.
J Cardiovasc Pharmacol. 1993 Jan;21(1):77-83. doi: 10.1097/00005344-199301000-00011.
Mexiletine, a class Ib antiarrhythmic drug, is used clinically as a racemic mixture of two enantiomers. Aromatic and aliphatic hydroxylation are the two major metabolic steps. In the liver, this metabolism is catalyzed by the cytochrome P450IID6, an isoenzyme of cytochrome P450 due to genetic polymorphism in humans. In the present study, the metabolism of the two stereoisomers was compared in vitro in human liver microsomes. Parahydroxylation (aromatic hydroxylation) is favored for S(+)-mexiletine with a mean intrinsic clearance higher than for R(-)-mexiletine. The R(-) enantiomer exhibits a threefold higher mean Vmax value for aliphatic hydroxylation than S(+)-mexiletine. We showed that (i) the high-affinity component of dextrometorphan O-demethylation was competitively inhibited by R(-)- and S(+)-mexiletine and that (ii) hydroxylations of the two enantiomers were very strongly competitively inhibited by quinidine. Hydroxylation reactions of mexiletine exhibit stereoselectivity in vitro in human liver microsomes and are catalyzed by P450IID6.
美西律是一种Ⅰb类抗心律失常药物，临床上使用的是两种对映体的外消旋混合物。芳香族和脂肪族羟基化是两个主要的代谢步骤。在肝脏中，这种代谢由细胞色素P450IID6催化，它是细胞色素P450的一种同工酶，因人类基因多态性而存在。在本研究中，在人肝微粒体中对两种立体异构体的代谢进行了体外比较。对于S(+)-美西律，对羟基化（芳香族羟基化）更有利，其平均内在清除率高于R(-)-美西律。R(-)对映体在脂肪族羟基化方面的平均Vmax值比S(+)-美西律高3倍。我们发现：(i)右美沙芬O-去甲基化的高亲和力成分受到R(-)-和S(+)-美西律的竞争性抑制，且(ii)两种对映体的羟基化受到奎尼丁的强烈竞争性抑制。美西律的羟基化反应在人肝微粒体中体外表现出立体选择性，且由P450IID6催化。
