Liu X Q, Ren Y L, Qian Z Y, Wang G J
Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
Acta Pharmacol Sin. 2000 Aug;21(8):690-4.
To study the enzyme kinetics of nimodipine (NDP) metabolism and the effects of selective cytochrome P-450 (CYP-450) inhibitors on the metabolism of NDP in human liver microsomes in vitro.
Microsomes from six individual human liver specimens were used to perform enzyme kinetic studies and the kinetic parameters were estimated by Eadie-Hofstee equation. Various selective CYP-450 inhibitors were used to investigate their effects on the metabolism of NDP and the principal CYP-450 isoform involved in dehydrogenation of dihydropyridine ring of NDP in human liver microsomes.
There was an important intersubject variability in NDP metabolism in human liver microsomes. For NDP dehydrogenase activity, the Km value was (36 +/- 11) mumol and the Vm value was (17 +/- 7) mumol.g-1.min-1. The dehydrogenation of dihydropyridine ring of NDP was competitively inhibited by ketoconazole (Ket) and troleandomycin (TAO), and the Ki values for Ket and TAO were 0.59 and 122.2 mumol, respectively. Phenacetin (Pnt), quinidine (Qui), diethyldithiocarbamate (DDC), sulfaphenazole (Sul), and tranylcypromine (Tra) had a little or no inhibitory effects on the dehydrogenation of NDP.
The intersubject variability of NDP pharmacokinetics was attributed to the metabolic polymorphism of NDP in liver. Cytochrome P-4503A (CYP3A) is involved in the dehydrogenation of dihydropyridine ring of NDP.
研究尼莫地平（NDP）代谢的酶动力学以及选择性细胞色素P-450（CYP-450）抑制剂对人肝微粒体中NDP代谢的影响。
使用来自六个个体人类肝脏标本的微粒体进行酶动力学研究，并通过伊迪-霍夫斯蒂方程估算动力学参数。使用各种选择性CYP-450抑制剂来研究它们对NDP代谢的影响以及参与人肝微粒体中NDP二氢吡啶环脱氢的主要CYP-450同工酶。
人肝微粒体中NDP代谢存在重要的个体间差异。对于NDP脱氢酶活性，Km值为（36±11）μmol，Vm值为（17±7）μmol·g-1·min-1。酮康唑（Ket）和三乙酰竹桃霉素（TAO）竞争性抑制NDP二氢吡啶环的脱氢，Ket和TAO的Ki值分别为0.59和122.2μmol。非那西丁（Pnt）、奎尼丁（Qui）、二乙基二硫代氨基甲酸盐（DDC）、磺胺苯唑（Sul）和反苯环丙胺（Tra）对NDP脱氢几乎没有抑制作用。
NDP药代动力学的个体间差异归因于肝脏中NDP的代谢多态性。细胞色素P-4503A（CYP3A）参与NDP二氢吡啶环的脱氢。
