Assessment of the potential drug-drug interaction between carvedilol and clopidogrel mediated through intestinal P-glycoprotein

The most widely prescribed oral antiplatelet agent, clopidogrel, shows high interindividual variability resulting in an increased risk of cardiovascular events in the patients with reduced platelet inhibition. The purpose of this study was to investigate the role of the P-glycoprotein (P-gp) efflux pump in limiting the intestinal permeability of clopidogrel and the effect of a beta-blocker, namely, carvedilol, on its intestinal transport. Effective permeabilities (P-eff) of clopidogrel and carvedilol were investigated in the proximal jejunum and distal ileum of rats using an in situ intestinal perfusion model. Peff values of clopidogrel and carvedilol were found to be concentration dependent with decreased P-eff values at the low perfusate concentrations. Coperfusion with the P-gp inhibitors verapamil (100 mu M) and carvedilol (10 mu M) significantly increased the P-eff of clopidogrel in the jejunum (8.31 +/- 0.20 x 10(-5) and 6.98 +/- 0.75 x 10(-5) vs. 3.60 +/- 0.51 x 10(-5), respectively) and ileum (9.08 +/- 2.19 x 10(-5) and 8.35 +/- 1.58 x 10-5 vs. 3.85 +/- 0.15 x 10(-5), respectively). However, at the highest concentration tested (30 mu M), clopidogrel exhibited 3 and 1.4 times higher P-eff than those of metoprolol, an FDA high permeability reference standard, in the jejunum and ileum, respectively. Overall, this study indicates that the efflux function appears not to have a significant impact on the in vivo intestinal absorption of clopidogrel due to the saturation of P-gp, suggesting no clinically relevant interaction between carvedilol and clopidogrel mediated through P-gp at intestinal level.