Lavrijsen K L, Van Houdt J M, Van Dyck D M, Hendrickx J J, Woestenborghs R J, Lauwers W, Meuldermans W E, Heykants J J
Department of Drug Metabolism and Pharmacokinetics, Janssen Research Foundation, Beerse, Belgium.
Anesthesiology. 1988 Oct;69(4):535-40. doi: 10.1097/00000542-198810000-00013.
The present study was designed to investigate whether the metabolism of the opiate analgesic alfentanil in humans is subject to the debrisoquine 4-hydroxylation polymorphism. The role of a specific cytochrome P-450 form, debrisoquine 4-hydroxylase, in the metabolism of alfentanil was investigated by competitive inhibition experiments over the concentration range 4-100 microM. Alfentanil was incubated with human liver microsomes in the presence of an NADPH-generating system. Alfentanil and its major metabolites were quantified in the incubates by reversed phase high-performance liquid chromatography (HPLC). Alfentanil was rapidly metabolized, yielding noralfentanil as the main metabolite. Kinetically, alfentanil metabolism occurred monophasically and the kinetic parameters were 22.8 microM for Km app and 3.86 nmol alfentanil metabolized min-1.mg protein-1 for Vm app. Debrisoquine was a weak, noncompetitive inhibitor of alfentanil metabolism and of the formation of its major metabolites, with Ki values between 2.00 and 3.21 mM. It can be concluded that alfentanil is not metabolized in vitro by the human cytochrome P-450 form involved in debrisoquine 4-hydroxylation; therefore, the in vivo disposition of the drug is most likely not affected by deficiency of this enzyme.
本研究旨在调查阿芬太尼这种阿片类镇痛药在人体内的代谢是否受异喹胍4-羟化多态性影响。通过在4 - 100微摩尔浓度范围内进行竞争性抑制实验，研究了一种特定的细胞色素P - 450形式，即异喹胍4 - 羟化酶，在阿芬太尼代谢中的作用。阿芬太尼在有NADPH生成系统存在的情况下与人肝微粒体一起孵育。通过反相高效液相色谱法（HPLC）对孵育物中的阿芬太尼及其主要代谢产物进行定量。阿芬太尼迅速代谢，产生去甲阿芬太尼作为主要代谢产物。从动力学角度看，阿芬太尼代谢呈单相进行，表观米氏常数（Km app）为22.8微摩尔，最大反应速度（Vm app）为每分钟每毫克蛋白代谢3.86纳摩尔阿芬太尼。异喹胍是阿芬太尼代谢及其主要代谢产物形成的一种弱的非竞争性抑制剂，抑制常数（Ki）值在2.00至3.21毫摩尔之间。可以得出结论，阿芬太尼在体外不会被参与异喹胍4 - 羟化的人细胞色素P - 450形式代谢；因此，该药物的体内处置很可能不受这种酶缺乏的影响。
