Inhibitory potencies of 1,4-dihydropyridine calcium antagonists to P-glycoprotein-mediated transport: comparison with the effects on CYP3A4.
OBJECTIVE
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.
Katoh
M
M
Division of Drug Metabolism, Faculty of Pharmaceutical Sciences, Kanazawa University, Japan.
Nakajima
M
M
Yamazaki
H
H
Yokoi
T
T
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002460:Cell Line; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003630:Daunorubicin / Q000493:pharmacokinetics; D004077:Digoxin / Q000493:pharmacokinetics; D004095:Dihydropyridines / Q000494:pharmacology*; D006801:Humans; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013379:Substrate Specificity; D014162:Transfection; D014316:Tritium
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002121:Calcium Channel Blockers; D065607:Cytochrome P-450 Enzyme Inhibitors; D004095:Dihydropyridines; D014316:Tritium; D004077:Digoxin; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D003630:Daunorubicin