IN-VITRO IDENTIFICATION OF THE HUMAN CYTOCHROME-P450 ENZYMES INVOLVEDIN THE METABOLISM OF R(-CARVEDILOL AND S(-)-CARVEDILOL())

Both the R(+) and the S(-) enantiomers of carvedilol were metabolized in human liver microsomes primarily to 4'-(4OHC) and 5'-(5OHC) hydroxy phenyl, 8-hydroxy carbazolyl (8OHC) and O-desmethyl (ODMC) derivatives , The S(-) enantiomer was metabolized faster than the R(+) enantiomer although the same P450 enzymes seemed to be involved in each case. A c ombination of multivariate correlation analysis, the use of selective inhibitors of P450, and microsomes from human lymphoblastoid cells exp ressing various human P450s enabled phenotyping of the enzymes involve d in the oxidative metabolism of carvedilol, CYP2D6 was primarily resp onsible for 4OHC and 5OHC production, although considerable activity w as observed in a CYP2D6 poor metabolizer liver and the variability of these activities across a human liver bank was not high, There was som e evidence that CYP2E1, CYP2C9, and CYP3A4 were also involved in the p roduction of these metabolites. CYP1A2 was primarily responsible for t he 8OHC pathway with additional contributions from CYP3A4, The ODMC wa s clearly associated with CYP2C9 with some evidence for the partial in volvement of CYP2D6, CYP1A2, and CYP2E1. With its complex P450 phenoty pe pattern and the known contribution of non-oxidative pathways of eli mination, the activity (or lack of activity) of any particular P450 wo uld have a limited influence on the disposition of carvedilol in an in dividual.