Inhibitory potencies of 1,4-dihydropyridine calcium antagonists to P-glycoprotein-mediated transport: comparison with the effects on CYP3A4

Purpose: Recently, we clarified the inhibitory effects of 13 kinds of 1,4-dihydropyridine calcium antagonists on human Cytochrome P450 (CYP) 3A4. It has been reported that the substrates and/or inhibitors are overlapped between CYP3A4 and P-glycoprotein (P-gp). The purpose of this study was to investigate the inhibitory effects of 13 kinds of 1,4-dihydropyridine calcium antagonists on P-gp-mediated transport in order to evaluate the overlapping specificity of the inhibitors between P-gp and CYP3A4.

Methods: The transcellular transports of [3H]daunorubicin or [3H]digoxin by monolayers of LLC-GA5-COL150 cells in which P-gp was overexpressed were measured in the presence or absence of the 1,4-dihydropyridine calcium antagonists.

Results: The transport of [3H]daunorubicin was strongly inhibited by manidipine, barnidipine, benidipine, (-)-efonidipine, nicardipine, (+)-efonidipine, and amlodipine with the IC50 values of 4.6, 8.6, 9.5, 17.3, 17.5, 20.6, and 22.0 microM, respectively. The transport of [3H]digoxin was strongly inhibited by benidipine, nicardipine, barnidipine, and manidipine.

Conclusions: It was clarified that 13 kinds of 1,4-dihydropyridine calcium antagonists have different inhibitory potencies and substrate specificities to the transport of [3H]daunorubicin or [3H]digoxin. Some compounds did not demonstrate the overlapping specificity for inhibition between P-gp and CYP3A4. It was also clarified that nicardipine, benidipine, manidipine, and barnidipine were strong inhibitors of P-gp as well as CYP3A4.