Interaction of angiotensin II type 1 receptor blockers with P-gp substrates in Caco-2 cells and hMDR1-expressing membranes.
OBJECTIVE
The inhibitory effect of angiotensin II type 1 receptor blockers (ARBs) on P-glycoprotein (P-gp) was examined to evaluate their clinical drug-drug interaction (DDI) potential.


METHODS
We performed an inhibition study on the vectorial transport of digoxin, a typical substrate for P-gp, using a human colonic adenocarcinoma cell line, Caco-2 cells, and verapamil-stimulated ATPase activity using human multidrug resistance 1 (hMDR1)-expressing membrane.


RESULTS
The vectorial transport of digoxin was inhibited by candesartan cilexetil, irbesartan and telmisartan with the IC(50) values of 14.7, 34.0 and 2.19microM, respectively. Those values were 7.4-426-fold higher than their theoretical clinical gastrointestinal concentration [I] at doses in clinical DDI studies. Other ARBs failed to show interaction with P-gp.


CONCLUSIONS
It was demonstrated that candesartan cilexetil, irbesartan and telmisartan had the potential to inhibit the transport of various drugs via P-gp. Telmisartan, which caused an increase in the serum digoxin concentration in humans, had a sufficiently high [I]/IC(50) value, suggesting that DDI between digoxin and telmisartan was caused by the inhibition of digoxin efflux via intestinal P-gp.
Kamiyama
Emi
E
Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58, Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. kamiyama.emi.gf@daiichisankyo.co.jp
Nakai
Daisuke
D
Mikkaichi
Tsuyoshi
T
Okudaira
Noriko
N
Okazaki
Osamu
O
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000251:Adenosine Triphosphatases / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology; D001565:Benzoates / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects*; D001713:Biphenyl Compounds / Q000494:pharmacology; D018938:Caco-2 Cells; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000378:metabolism*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D004077:Digoxin / Q000378:metabolism*; D004347:Drug Interactions; D006801:Humans; D000077405:Irbesartan; D019808:Losartan / Q000494:pharmacology; D000077333:Telmisartan; D013777:Tetrazoles / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001565:Benzoates; D001713:Biphenyl Compounds; D002121:Calcium Channel Blockers; D002316:Cardiotonic Agents; D013777:Tetrazoles; D004077:Digoxin; D014700:Verapamil; D000251:Adenosine Triphosphatases; D000077405:Irbesartan; D019808:Losartan; C077793:candesartan cilexetil; C081643:candesartan; D000077333:Telmisartan