Enzyme kinetics and inhibition of nimodipine metabolism in human liver microsomes

AIM: To study the enzyme kinetics of nimodipine (NDP) metabolism and the ef fects of selective cytochrome P-450 (CYP-450) inhibitors on the metabolism of NDP in human liver microsomes lit vitro. METHODS: Microsomes from six in dividual human liver specimens were used to perform enzyme kinetic studies and the kinetic parameter; were estimated by Eadie-Hofstee equation. Variou s selective CYP-450 inhibitors were used to investigate their effects on th e metabolism of NDP and the principal CYP-450 isoform involved in dehydroge nation of dihydropyridine ring of NDP in human liver microsomes. RESULTS: T here was an important intersubject variability in NDP metabolism in human l iver microsomes. For NDP dehydrogenase activity, the K-m value was (36 +/- 11) mu mol and the V-m value was (11 +/- 7) mu ol.g(-1).min(-1). The dehydr ogenation of dihydropyridine ring of MDP was competitively inhibited by ket oconazole (Ket) and troleandomycin (TAO), and the K-i values for Ket and TA O were 0.59 and 122.2 mu mol, respectively. Phenacetin (Pnt), quinidine (Qu i), diethyldithiocarbamate (DDC), sulfaphenazole (Sul), and tranylcypromine (Tra) had a little or no inhibitory effects on the dehydrogenation of NDP. CONCLUSION: The intersubject variability of NDP pharmacokinetics was attri buted to the metabolic polymorphism of NDP in liver. Cytochrome P-4503A (CY P3A) is involved in the dehydrogenation of dihydropyridine ring of NDP.