Metabolism and metabolic inhibition of cilnidipine in human liver microsomes.
OBJECTIVE
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 alpha-naphthoflavone (alpha-Naph), sulfaphenazole (Sul), quinidine (Qui), diethyldithiocarbamate (DDC), and tranylcypromine (Tra) had a little or no inhibitory effects on the dehydrogenation of cilnidipine.


CONCLUSIONS
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.
Liu
Xiao-Quan
XQ
Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009. Liuxq@Jlonline.com
Zhao
Yang
Y
Li
Dan
D
Qian
Zhi-Yu
ZY
Wang
Guang-Ji
GJ
D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D004095:Dihydropyridines / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D007654:Ketoconazole / Q000494:pharmacology*; D008862:Microsomes, Liver / Q000378:metabolism*; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors
D065607:Cytochrome P-450 Enzyme Inhibitors; D004095:Dihydropyridines; C065927:cilnidipine; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D007654:Ketoconazole