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目的:在体外研究人肝微粒体中尼莫地平代谢的酶动力学及选择性的细胞色素P-450(CYP450)酶抑制剂对尼莫地平代谢的影响。方法:采用人肝微粒体研究尼莫地平脱氢酶的代谢动力学,运用Eadie-Hof-stee方程估算其动力学参数。在体外运用CYP450酶的选择性抑制剂探讨其对尼莫地平代谢的影响及人肝微粒体中参与尼莫地平二氢吡啶环脱氢代谢的CYP450酶。结果:尼莫地平在人肝微粒体中的代谢存在较大的个体差异,尼莫地平脱氢酶的K_m为(36±11)μmol,其V_m为(17±7)μmol·g~(-1)·min~(-1)。酮康唑和三乙酰竹桃霉素竞争性地抑制尼莫地平二氢吡啶环脱氢代谢,其K_i值分别为0.59和122.2μmol。非那西丁、奎尼丁、DDC、Sul和Tra对尼莫地平二氢吡啶环脱氢代谢没有明显的影响。结论:尼莫地平在体内的药物动力学个体差异与其在肝中的代谢存在多态性有关。CYP3A参与了尼莫地平二氢吡啶环脱氢代谢,CYP3A的抑制剂可能会与尼莫地平发生代谢相互作用。
OBJECTIVE: To study the enzyme kinetics of nimodipine metabolism in human liver microsomes and the effects of selective inhibitors of cytochrome P-450 (CYP450) on the metabolism of nimodipine in vitro. Methods: The kinetics of nimodipine dehydrogenase was studied using human liver microsomes. The kinetic parameters were estimated using the Eadie-Hof-stee equation. In vitro use of selective inhibitors of CYP450 enzyme to explore the impact of its metabolism on nimodipine and human liver microsomal CYP450 enzymes involved in nimodipine dihydropyridine ring dehydrogenation. Results: There was a large individual difference in the metabolism of nimodipine in human liver microsome. The Km of nimodipine dehydrogenase was (36 ± 11) μmol and the Vm was 17 ± 7 μmol · g ~ (- 1) · min ~ (-1). Ketoconazole and triacetylsetimomycin competitively inhibited the dehydrogenation of the nimodipine ring with K_i values of 0.59 and 122.2 μmol, respectively. Phenacetin, quinidine, DDC, Sul and Tra had no significant effect on the dehydrogenation of nimodipine ring. CONCLUSIONS: Individual differences in nimodipine pharmacokinetics in vivo correlate with its polymorphism in the liver metabolism. CYP3A is involved in the dehydrogenative metabolism of the dihydropyridyl ring of nimodipine, and CYP3A inhibitors may have metabolic interactions with nimodipine.