Species differences of inhibitory effects on P-glycoprotein-mediated drug transport.
Previously, we clarified the species differences in P-glycoprotein (P-gp)-mediated drug transport activity using human MDR1, monkey MDR1, canine MDR1, rat MDR1a, rat MDR1b, mouse mdr1a, and mouse mdr1b transfected LLC-PK(1) cell lines. However, the species differences in the inhibitory effects on P-gp-mediated drug transport have not been clarified yet. The purpose of the present study was to evaluate the species differences in the inhibitory effects of typical P-gp inhibitors, quinidine and verapamil, on P-gp-mediated drug transport using MDR1 transfected cell lines. The transcellular transport of [(3)H]daunorubicin, [(3)H]digoxin, and [mebmt-beta-(3)H]cyclosporin A across monolayers of the MDR1 transfected cells were measured in the presence or absence of P-gp inhibitors. On daunorubicin transport, the relative IC(50) value (quinidine IC(50)/verapamil IC(50)) of human P-gp was 5.25 and those from other species ranged from 0.89 to 10.70. The transport of digoxin and cyclosporin A also showed different relative IC(50) values among human, monkey, canine, rat, and mouse P-gps. The present study revealed that species differences in the inhibitory effects on P-gp-mediated drug transport should not be disregarded among human, monkey, canine, rat, and mouse. This study will provide useful information for predicting drug interactions mediated by P-gp.
Suzuyama
Naoto
N
Drug Metabolism and Toxicology, Division of Pharmaceutical Sciences, Graduate School of Medical Science, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.
Katoh
Miki
M
Takeuchi
Toshiyuki
T
Yoshitomi
Sumie
S
Higuchi
Tomoaki
T
Asashi
Satoru
S
Yokoi
Tsuyoshi
T
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000502:physiology; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D016572:Cyclosporine / Q000493:pharmacokinetics; D003630:Daunorubicin / Q000493:pharmacokinetics; D004077:Digoxin / Q000493:pharmacokinetics; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006801:Humans; D051379:Mice; D011802:Quinidine / Q000494:pharmacology*; D051381:Rats; D013045:Species Specificity; D014700:Verapamil / Q000494:pharmacology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004077:Digoxin; D016572:Cyclosporine; D014700:Verapamil; D011802:Quinidine; D003630:Daunorubicin