Abstract

Both the R(+) and the S(−) enantiomers of carvedilol were metabolized in human liver microsomes primarily to 4′- (4OHC) and 5′- (5OHC) hydroxyphenyl, 8-hydroxy carbazolyl (8OHC) andO-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 combination of multivariate correlation analysis, the use of selective inhibitors of P450, and microsomes from human lymphoblastoid cells expressing various human P450s enabled phenotyping of the enzymes involved in the oxidative metabolism of carvedilol. CYP2D6 was primarily responsible for 4OHC and 5OHC production, although considerable activity was observed in a CYP2D6 poor metabolizer liver and the variability of these activities across a human liver bank was not high. There was some evidence that CYP2E1, CYP2C9, and CYP3A4 were also involved in the production of these metabolites. CYP1A2 was primarily responsible for the 8OHC pathway with additional contributions from CYP3A4. The ODMC was clearly associated with CYP2C9 with some evidence for the partial involvement of CYP2D6, CYP1A2, and CYP2E1. With its complex P450 phenotype pattern and the known contribution of non-oxidative pathways of elimination, the activity (or lack of activity) of any particular P450 would have a limited influence on the disposition of carvedilol in an individual.