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

The purpose of this study was to determine whether an enantioselective diff erence in the metabolism of topically applied R-(-)- and S-(+)-carvone coul d be observed in man. In a previous investigation we found that R-(-)- and S-(+)-carvone are stereoselectively biotransformed by human liver microsome s to 4R,6S-(-)- and 4S,6S-(+)-carveol, respectively, and 4R,6S-(-)-carveol is further glucuronidated. We therefore investigated the metabolism and pha rmacokinetics of R-(-)- and S-(+)-carvone in four healthy subjects using ch iral gas chromatography as the analytical method. Following separate topica l applications at a dose of 300 mg, R-(-)- and S-(+)-carvone were rapidly a bsorbed, resulting in significantly higher C-max levels for S-(+)-carvone ( 88.0 vs 23.9 ng mL(-1)) and longer distribution half-lives (t(2 alpha)(1)) (19.4 vs 7.8 min), resulting in 3.4-fold higher areas under the blood conce ntration-time curves (5420 vs 1611 ng min mL(-1)). The biotransformation pr oducts for both enantiomers in plasma were below detection limit. Analysis of control- and beta -glucuronidase pretreated urine samples, however, reve aled a stereoselective metabolism of R-(-)-carvone to 4R,6S-(-)-carveol and 4R,6S-(-)-carveol glucuronide. No metabolites could be found in urine samp les after S-(+)carvone application. These data indicate that stereoselectiv ity in phase-I and phase-II metabolism has significant effects on R-(-)- an d S-(+)-carvone pharmacokinetics, This might serve to explain the increased blood levels of S-(+)-carvone.