Enzyme kinetics and inhibition of nimodipine metabolism in human liver microsomes

AIM: 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. METHODS: 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. RESULTS: There was an important intersubject variability in NDP metabolism in human liver microsomes. For NDP dehydrogenase activity, the K(m) value was (36 ± 11) μmol and the V(m) value was (17 ± 7) μmol · g^-1 · min^-1. The dehydrogenation of dihydropyridine ring of NDP was competitively inhibited by ketoconazole (Ket) and troleandomycin (TAO), and the K₁ values for Ket and TAO were 0.59 and 122.2/μmol, respectively. Phenacetin (Pnt), quinidine (Qui), 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 attributed to the metabolic polymorphism of NDP in liver. Cytochrome P-4503A (CYP3A) is involved in the dehydrogenation of dihydropyridine ring of NDP.