TY - JOUR T1 - Stereoselective First-Pass Metabolism of Verapamil in the Small Intestine and Liver in Rats JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 2037 LP - 2042 DO - 10.1124/dmd.107.020339 VL - 36 IS - 10 AU - Kazuhiko Hanada AU - Yasutaka Ikemi AU - Kazutaka Kukita AU - Kiyoshi Mihara AU - Hiroyasu Ogata Y1 - 2008/10/01 UR - http://dmd.aspetjournals.org/content/36/10/2037.abstract N2 - Verapamil (VP) 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 VP and its main metabolite, norverapamil (NVP). VP racemate was administered to rats i.v., p.o., and via the portal vein. The formation rates of the main metabolites of the VP enantiomers were estimated in an in vitro intestinal microsomal study. The hepatic bioavailability of VP showed saturable metabolism, and the hepatic bioavailability of R-VP was higher than that of S-VP. Conversely, the intestinal bioavailability of R-VP was lower than that of S-VP, resulting in a higher systemic bioavailability of S-VP. The pharmacokinetics of the NVP enantiomers was similar. These results suggest that the stereoselectivity of the total bioavailability of VP is determined by first-pass metabolism in the small intestine and liver, and that the NVP enantiomers observed in the systemic circulation after p.o. administration of VP racemate originate mainly from the liver in rats. The American Society for Pharmacology and Experimental Therapeutics ER -