| 19914261 |
Kamiyama E, Nakai D, Mikkaichi T, Okudaira N, Okazaki O: Interaction of angiotensin II type 1 receptor blockers with P-gp substrates in Caco-2 cells and hMDR1-expressing membranes. Life Sci. 2010 Jan 2;86(1-2):52-8. Epub 2009 Nov 13.
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 2.19microM, 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. 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. |
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