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• W1813868210 abstract "Methadone was first approved for clinical use in the United States in 1972. It is currently indicated for the treatment of moderate to severe pain, for detoxification of opiate addiction, and for maintenance treatment of individuals with opiate dependence. “Since the metabolism of methadone is mediated primarily by CYP3A4 isozyme, coadministration of drugs that inhibit CYP3A4 activity may cause decreased clearance of methadone. The expected clinical results would be increased or prolonged opiate effects. Thus, methadone-treated patients coadministered strong inhibitors of CYP3A4, such as azole antifungal agents (e.g., ketoconazole) and macrolide antibiotics (e.g., erythromycin), with methadone should be carefully monitored, and dosage adjustments should be undertaken if warranted.” The inferred role of CYP3A isoforms in methadone clearance probably arises from earlier in vitro studies, going back as far as 1996.1-7 With the evolution of in vitro methodology over the last two decades, it has become evident that these studies in fact did not establish CYP3A as the predominant enzyme mediating methadone clearance. Limitations of the studies include: 1. Non-consideration of CYP2B6 as a possible contributing CYP isoform; 2. Use of methadone concentrations far exceeding the usual clinical range; 3. Use of index inhibitor concentrations exceeding the range of specificity; 4. Use of only recombinant CYP3A4 in the studies. More recent in vitro studies have established that CYP2B6, not CYP3A, is the predominant CYP isoform mediating clearance of methadone, and particularly of the pharmacologically active enantiomer (S-methadone).8-10 Clinical drug interaction studies involving methadone support the predominant role of CYP2B6 in methadone clearance. Much of this work has been conducted by Dr. Evan D. Kharasch and associates. Specific components of evidence include the following. Acute exposure to established CYP3A inhibitors – including ritonavir, nelfinavir, troleandomycin, and grapefruit juice – produced negligible inhibition of methadone clearance,11-16 whereas clearance of an established CYP3A index substrate (such as alfentanil) under the same conditions was greatly impaired. In contrast, acute exposure to the CYP2B6 inhibitor, ticlopidine, impaired S-methadone clearance, but had no effect on clearance of the CYP3A index substrate, alfentanil.17 Finally, acute exposure to ritonavir did not impair clearance of bupropion, an index substrate used to profile CYP2B6 metabolic activity.18 In extended exposure studies, more prolonged treatment with ritonavir-containing antiretroviral treatment combinations, or to nelfinavir alone, caused a reduction in methadone plasma concentrations, consistent with induction of methadone metabolism.13-16, 19-22 However, clearance of a CYP3A index substrate was significantly inhibited, indicating that enhanced clearance of methadone is not attributable to CYP3A. Extended exposure to indinavir, a less potent inducer, had little effect on methadone clearance, but caused extensive impairment of clearance of the index CYP3A substrate.23 The inevitable conclusion is that clearance of methadone in humans is mediated mainly by CYP2B6, not CYP3A. Induced clearance of methadone due to extended exposure to a number of antiretroviral drugs is most likely explained by induction of CYP2B6.24 While some review articles acknowledge the role of CYP2B6 in methadone clearance,25 others hold to the incorrect notion.26-28 We hope that the regulatory authorities will take the initiative to revise the product label, and that the correct information will be taken up by scholarly reviewers. —David J. Greenblatt, MD, Editor-in-Chief Tufts University School of Medicine Boston, Massachusetts 02111" @default.
• W1813868210 created "2016-06-24" @default.
• W1813868210 creator A5087737186 @default.
• W1813868210 date "2014-07-01" @default.
• W1813868210 modified "2023-10-09" @default.
• W1813868210 title "Drug interactions with methadone: Time to revise the product label" @default.
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• W1813868210 doi "https://doi.org/10.1002/cpdd.137" @default.
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