Percutaneous absorption of the montoterpene carvone: implication of stereoselective metabolism on blood levels

Abstract

The purpose of this study was to determine whether an enantioselective difference in the metabolism of topically applied R-(—)- and S-(+)-carvone could be observed in man. In a previous investigation we found that R-(—)- and S-(+)-carvone are stereoselectively biotransformed by human liver microsomes to 4R,6S-(—)- and 4S,6S-(+)-carveol, respectively, and 4R,6S-(—)-carveol is further glucuronidated. We therefore investigated the metabolism and pharmacokinetics of R-(—)- and S-(+)-carvone in four healthy subjects using chiral gas chromatography as the analytical method. Following separate topical applications at a dose of 300 mg, R-(—)- and S-(+)-carvone were rapidly absorbed, resulting in significantly higher Cmax levels for S-(+)-carvone (88.0 vs 23.9 ng mL−1) and longer distribution half-lives (t2α1) (19.4 vs 7.8 min), resulting in 3.4-fold higher areas under the blood concentration-time curves (5420 vs 1611 ng min mL−1). The biotransformation products for both enantiomers in plasma were below detection limit. Analysis of control- and β-glucuronidase pretreated urine samples, however, revealed a stereoselective metabolism of R-(—)-carvone to 4R,6S-(—)-carveol and 4R,6S-(—)-carveol glucuronide. No metabolites could be found in urine samples after S-(+)-carvone application. These data indicate that stereoselectivity in phase-I and phase-II metabolism has significant effects on R-(—)- and S-(+)-carvone pharmacokinetics. This might serve to explain the increased blood levels of S-(+)-carvone.