In vitro identification of the human cytochrome P450 enzymes involved in the metabolism of R(+)- and S(-)-carvedilol.

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Oldham HG, Clarke SE

In vitro identification of the human cytochrome P450 enzymes involved in the metabolism of R(+)- and S(-)-carvedilol.

Drug Metab Dispos. 1997 Aug;25(8):970-7.

PubMed ID

9280405 [ View in PubMed

]

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) 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.

DrugBank Data that Cites this Article

Drugs

Carvedilol

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Carvedilol	Cytochrome P450 1A2	Protein	Humans	Unknown	Substrate	Details
Carvedilol	Cytochrome P450 2E1	Protein	Humans	Unknown	Substrate	Details
Carvedilol	Cytochrome P450 3A4	Protein	Humans	Unknown	Substrate	Details

Drug Reactions

Reaction
Carvedilol DB01136 Cytochrome P450 1A2 Cytochrome P450 3A4 Cytochrome P450 1A1 8-Hydroxycarbazolylcarvedilol DBMET00115	Details
Carvedilol DB01136 Cytochrome P450 2D6 Cytochrome P450 2E1 Cytochrome P450 2C9 Cytochrome P450 3A4 4'-Hydroxyphenylcarvedilol DBMET00116	Details
Carvedilol DB01136 Cytochrome P450 2D6 Cytochrome P450 2C9 Cytochrome P450 3A4 5'-Hydroxyphenylcarvedilol DBMET00117	Details
Carvedilol DB01136 Cytochrome P450 2C9 Cytochrome P450 2D6 Cytochrome P450 1A2 Cytochrome P450 2E1 O-Desmethylcarvedilol DBMET00118	Details
Carvedilol DB01136 Prostaglandin G/H synthase 1 Cytochrome P450 2D6 Cytochrome P450 1A2 Cytochrome P450 1A1 1-Hydroxyphenylcarvedilol DBMET00119	Details