digoxin and candesartan

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.. 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.. 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.. 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.

Topics: Adenosine Triphosphatases; Angiotensin II Type 1 Receptor Blockers; ATP Binding Cassette Transporter, Subfamily B, Member 1; Benzimidazoles; Benzoates; Biological Transport; Biphenyl Compounds; Caco-2 Cells; Calcium Channel Blockers; Cardiotonic Agents; Cell Membrane; Digoxin; Drug Interactions; Humans; Irbesartan; Losartan; Telmisartan; Tetrazoles; Verapamil