Interaction of methadone with substrates of human hepatic cytochrome P450 3A4.
Methadone, a synthetic drug, is one of the most widely used drugs for opiate dependency treatment. This drug has been demonstrated to be extensively 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 Ki of 100 microM. Fluvoxamine, a new antidepressant, was shown to be a potent mixed-type inhibitor of methadone N-demethylation with a Ki of 7 microM. Finally, methadone appears to be a mixed-type inhibitor and not a suicide inhibitor of cytochrome P450 3A family. Accordingly, caution should be advised in the clinical use of methadone when other drugs are administered that are able to induce or inhibit P450 3A4, such as rifampicin or nifedipine, diazepam and fluvoxamine.
Iribarne
C
C
Equipe d'Accueil EA 948, Laboratoires de Biochimie-Nutrition, Faculté de médecine, Brest, France.
Dréano
Y
Y
Bardou
L G
LG
Ménez
J F
JF
Berthou
F
F
D001667:Binding, Competitive / Q000187:drug effects; D019363:Cytochrome P-450 CYP1A1 / Q000032:analysis; D019362:Cytochrome P-450 CYP2B1 / Q000032:analysis; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism* / Q000494:pharmacology*; D003915:Dextromethorphan / Q000378:metabolism; D003975:Diazepam / Q000494:pharmacology; D016666:Fluvoxamine / Q000494:pharmacology; D006801:Humans; D008691:Methadone / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology*; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology*; D009543:Nifedipine / Q000494:pharmacology; D012293:Rifampin / Q000494:pharmacology
D065607:Cytochrome P-450 Enzyme Inhibitors; D003915:Dextromethorphan; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D019363:Cytochrome P-450 CYP1A1; D019362:Cytochrome P-450 CYP2B1; D051544:Cytochrome P-450 CYP3A; D009543:Nifedipine; D016666:Fluvoxamine; D003975:Diazepam; D008691:Methadone; D012293:Rifampin