Abstract
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.
Footnotes
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This work was supported in part by a grant from the Japan Research Foundation for Clinical Pharmacology.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.107.020339.
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ABBREVIATIONS: VP, verapamil; NVP, norverapamil; AUC, area under the drug concentration-time curve; HPLC, high-performance liquid chromatography; B/P, blood to plasma concentration.
- Received December 27, 2007.
- Accepted July 9, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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