Enzyme kinetics and inhibition of nimodipine metabolism in human liver microsomes.
OBJECTIVE
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 Km value was (36 +/- 11) mumol and the Vm value was (17 +/- 7) mumol.g-1.min-1. The dehydrogenation of dihydropyridine ring of NDP was competitively inhibited by ketoconazole (Ket) and troleandomycin (TAO), and the Ki values for Ket and TAO were 0.59 and 122.2 mumol, respectively. Phenacetin (Pnt), quinidine (Qui), diethyldithiocarbamate (DDC), sulfaphenazole (Sul), and tranylcypromine (Tra) had a little or no inhibitory effects on the dehydrogenation of NDP.


CONCLUSIONS
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.
Liu
X Q
XQ
Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China. Liuxq@Jlonline.com
Ren
Y L
YL
Qian
Z Y
ZY
Wang
G J
GJ
D002121:Calcium Channel Blockers / Q000378:metabolism / Q000493:pharmacokinetics; D006801:Humans; D066298:In Vitro Techniques; D007654:Ketoconazole / Q000494:pharmacology*; D008862:Microsomes, Liver / Q000378:metabolism*; D009553:Nimodipine / Q000378:metabolism* / Q000493:pharmacokinetics*; D014217:Troleandomycin / Q000494:pharmacology*
D002121:Calcium Channel Blockers; D009553:Nimodipine; D014217:Troleandomycin; D007654:Ketoconazole