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)-Carvedilol
Drug Metabolism and Pharmacokinetics, SmithKline Beecham
Pharmaceuticals
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) 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 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.
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