Methadone, a synthetic drug, is one of the most widely used drugs for
opiate dependency treatment. This drug has been demonstrated to be ext
ensively metabolized by cytochrome P450 3A4 in human liver microsomes.
Thus, the aim of this in vitro study was to determine if methadone is
an inhibitor of other P450s characterized by their specific catalytic
activities. Enzymatic activities specific to P450 2E1, P450 1A, P450
2B and P450 2C were not inhibited by methadone. Conversely, nifedipine
oxidation, mediated by cytochrome P450 3A4, was potently inhibited by
methadone by a mixed-type inhibition mechanism with a K-i of 100 mu M
. Fluvoxamine, a new antidepressant, was shown to be a potent mixed-ty
pe inhibitor of methadone N-demethylation with a K-i of 7 mu M. Finall
y, methadone appears to be a mixed-type inhibitor and not a suicide in
hibitor of cytochrome P450 3A family. Accordingly, caution should be a
dvised in the clinical use of methadone when other drugs are administe
red that are able to induce or inhibit P450 3A4, such as rifampicin or
nifedipine, diazepam and fluvoxamine. Copyright (C) 1997 Elsevier Sci
ence Ireland Ltd.