Effect of intestinal first‐pass hydrolysis on the oral bioavailability of an ester prodrug of fexofenadine

ABSTRACT: The contribution of intestinal first-pass hydrolysis to oral bioavailability was evaluated in rats using a model prodrug of fexofenadine (FXD), which has poor oral bioavailability. The prodrug, ethyl-FXD, has high membrane permeability but the oral bioavailability of FXD derived from ethyl-FXD was only 6.2%. Ethyl-FXD was not detected in the plasma, whereas FXD was detected, indicating complete first-pass hydrolysis. In in vitro experiments, hydrolase activity for ethyl-FXD was higher in the liver and blood than that in the intestine. However, the high blood protein binding of ethyl-FXD resulted in a high hepatic availability ( F h = 88%). The complete bioconversion of ethyl-FXD in the in vivo oral administration is difficult to explain by first-pass hydrolysis in the liver and blood. Interestingly, in an in situ rat jejunal single-pass perfusion experiment, 84% of the ethyl-FXD taken up into enterocytes was hydrolyzed. Furthermore, only one-fifth of the FXD formed in mucosa reached the mesenteric vein because of its P-glycoprotein-mediated efflux into the intestinal lumen. These findings indicate that the intestinal bioconversion of ester prodrugs to their parent drugs is a key factor in determining their oral bioavailability. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:3264–3274, 2012