Screening for inhibitory effects of antineoplastic agents on CYP3A4 in human liver microsomes.

Background: The human cytochrome P450 enzyme CYP3A4 is involved in the metabolism of many anticancer drugs. Since these drugs are usually administered in a polychemotherapy regimen, the objective of this study was to examine their inhibitory potency on CYP3A4 with regard to possible mutual drug interactions.

Method: CYP3A4 activities in human liver microsomes from 2 donors were determined using the oxidation of the dihydropyridine denitronifedipine, a specific CYP3A4 substrate, at a concentration of 50 microM (= KM).

Dihydropyridine enantiomers block recombinant L-type Ca2+ channels by two different mechanisms.

1. The molecular basis of the state-dependent block of L-type Ca2+ channels by dihydropyridines is still poorly understood. Therefore, we studied the enantioselectivity of Ca2+ channel block by isradipine enantiomers at three holding potentials (-80, -60 and -40 mV) in Chinese hamster ovary (CHO) cells stably expressing the rabbit lung alpha1C-b-subunit.