Metabolism and metabolic inhibition of cilnidipine in human liver microsomes

AIM: To study the metabolism of cilnidipine and the effects of selective cytochrome P-450 (CYP450) inhibitors on the metabolism of cilnidipine in human liver microsomes in vitro. METHODS: Human liver microsomes were used to perform metabolism studies. Various selective CYP450 inhibitors were used to investigate their effects on the metabolism of cilnidipine and the principal CYP450 isoform involved in dehydrogenation of dihydropyridine ring of cilnidipine in human liver microsomes. RESULTS: Cilnidipine was rapidly metabolized to three metabolites. They are dehydrogenated metabolite of dihydropyridine ring of cilnidipine (M₁), demethylation metabolite of lateral chain of dihydropyridine ring of cilnidipine (M₂), and the dehydrogenation and demethylation metabolite of cilnidipine (M₃). Ketoconazole (Ket) competitively inhibited the dehydrogenation of dihydropyridine ring of cilnidipine and lowered the metabolic rate of cilnidipine while α-naphthoflavone (α-Naph), sulfaphenazole (Sul), quinidine (Qui), diethyldithiocarbamate (DDC), and tranylcypromine (Tra) had a little or no inhibitory effects on the dehydrogenation of cilnidipine. CONCLUSION: Cilnidipine was rapidly metabolized in human liver microsomes and dehydrogenation of dihydropyridine ring of cilnidipine is crucial for the elimination of cilnidipine. Cytochrome P-4503A (CYP3A) is the major human CYP involved in the dehydrogenation of dihydropyridine ring of cilnidipine.