Journal
LIFE SCIENCES
Volume 86, Issue 1-2, Pages 52-58Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.lfs.2009.11.006
Keywords
Drug-drug interaction; P-gp; ARB; Intestine; IC(50)
Ask authors/readers for more resources
Aims: 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. Main 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. Key findings: The vectorial transport of digoxin was inhibited by candesartan cilexetil, irbesartan and telmisartan with the IC(50) values of 14.7. 34.0 and 2.19 mu M, 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. Significance: 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. (C) 2009 Elsevier Inc. All rights reserved.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available