Received for publication December 28, 2007.
Revised July 9, 2008.
Accepted for publication July 9, 2008.

Stereoselective first-pass metabolism of verapamil in the small intestine and liver in rats

Abstract

Verapamil is used as a racemate, but shows stereoselective pharmacokinetics and pharmacodynamics. It undergoes extensive first-pass metabolism. Stereoselective first-pass metabolism in the intestine and liver was investigated in vivo and in vitro to determine its impact on the disposition of verapamil and its main metabolite, norverapamil. Verapamil racemate was administered to rats intravenously, orally and via the portal vein. The formation rates of the main metabolites of the verapamil enantiomers were estimated in an in vitro intestinal microsomal study. The hepatic bioavailability of verapamil showed saturable metabolism and the hepatic bioavailability of R- verapamil was higher than that of S- verapamil. Conversely, the intestinal bioavailability of R- verapamil was lower than that of S- verapamil, resulting in a higher systemic bioavailability of S- verapamil. The pharmacokinetics of the norverapamil enantiomers were similar. These results suggest that the stereoselectivity of the total bioavailability of verapamil is determined by first-pass metabolism in the small intestine and liver, and that the norverapamil enantiomers observed in the systemic circulation after oral administration of verapamil racemate originate mainly from the liver in rats.

Key words: absorption, bioavailability, metabolite kinetics, microsomes, protein binding