Methadone Metabolism and Drug-Drug Interactions: In Vitro and In Vivo Literature Review

Volpe, Donna A.; Xu, Yun; Sahajwalla, Chandrahas; Younis, Islam R.; Patel, Vikram

doi:10.1016/j.xphs.2018.08.025

Cited by 48 publications

(36 citation statements)

References 88 publications

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“…It has been reported that ketoconazole, itraconazole, and voriconazole could inhibit the metabolism of imatinib and carvedilol by effecting on CYP3A4 . Simultaneously, it has been reported that methadone is mainly metabolized through CYP3A4 . Therefore, our in vitro results are well in accordance with the pharmacokinetics study in vivo, indicating that the change of C max , AUC, and CL may be caused by the inhibitory effect on CYP3A4.…”

Section: Discussionsupporting

confidence: 87%

“…Methadone metabolism is catalyzed mainly by CYP3A4, and partly by CYP2D6 and CYP3A4. Inhibition of the metabolic enzymes could improve the systemic exposure of methadone and alter pharmacokinetics …”

Section: Discussionmentioning

confidence: 99%

“…Inhibition of the metabolic enzymes could improve the systemic exposure of methadone and alter pharmacokinetics. 25 Methadone taken orally is subjected to an important first-pass effect and is detectable in the plasma about 30 minutes after administration. 26,27 Its bioavailability varies from 41-76% to 85-95%.…”

Section: Discussionmentioning

confidence: 99%

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Inhibitory effect of isavuconazole, ketoconazole, and voriconazole on the pharmacokinetics of methadone in vivo and in vitro

Shen

Wang

et al. 2018

Drug Testing and Analysis

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The aim of this study was to investigate the possible effect of orally administered isavuconazole, ketoconazole, or voriconazole on the pharmacokinetics of methadone in rats. Twenty Sprague–Dawley (SD) rats were divided randomly into four groups: Group A (control), group B (5 mg/kg isavuconazole), group C (5 mg/kg ketoconazole), and group D (5 mg/kg voriconazole). A single dose of methadone was administrated half an hour later. Methadone in plasma concentrations and its metabolite EDDP in microsomes were determined by ultra‐high‐performance liquid chromatography–tandem mass spectrometry method (UPLC–MS/MS), and pharmacokinetic parameters were calculated by DAS version 3.0. The Cmax of methadone in groups C and D increased to 2.7‐fold and 5‐fold, respectively. While AUC increased in three groups and group D increased the most. Also, isavuconazole, ketoconazole, and voriconazole showed inhibitory effect on human and rat microsomes. The inhibition ratios of isavuconazole, ketoconazole, and voriconazole in rat liver microsome were 97.87%, 96.74% and 78.9%, respectively (p < 0.01), while in human liver microsome, inhibition ratios were 86.97%, 96.46%, and 53.11%, respectively. And the IC50 for inhibition activity of isavuconazole, ketoconazole, and voriconazole in rat microsomes were 7.76 μM, 8.33 μM, and 4.45 μM, respectively. Our study indicated that taking methadone combine with ketoconazole, isavuconazole, or voriconazole could reduce the metabolism rate of methadone and prolong the pharmacological effects in vivo and in vitro.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

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Inhibitory effect of isavuconazole, ketoconazole, and voriconazole on the pharmacokinetics of methadone in vivo and in vitro

Shen

Wang

et al. 2018

Drug Testing and Analysis

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“…Achieving target therapeutic dosages, however, must occur slowly with careful monitoring as methadone prolongs the QTc interval, increasing risk for fatal ventricular arrhythmias, and has multiple drug-drug interactions due to its complex metabolism [18]. Methadone has high oral bioavailability, and undergoes N -demethylation via multiple CYP enzymes [19]. Methadone metabolism, therefore, may be altered by inhibitors and inducers of these multiple CYP enzymes.…”

Section: Methadonementioning

confidence: 99%

“…Patients on nevirapine, efavirenz, and ritonavir, as well as lopinavir/ritonavir and darunavir/ritonavir combinations may require higher methadone doses. There may also be significant effects on the metabolism of antiretrovirals by methadone, zidovudine in particular, potentially requiring dose-adjustment [19, 20]. Outside of ART, there are other commonly prescribed medications that interact with methadone.…”

Section: Methadonementioning

confidence: 99%

Medications for Treatment of Opioid Use Disorder among Persons Living with HIV

2019

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Purpose of Review Recent HIVoutbreaks have occurred as a result of the current US opioid epidemic. Providing medications for opioid use disorder (MOUD) with methadone, buprenorphine, and extended-release naltrexone is essential to achieving optimal HIV treatment outcomes including viral suppression and retention in treatment. This review describes the pharmacology of MOUD with specific attention to interactions with antiretroviral therapy, and to the effect of MOUD on HIV treatment outcomes. Recent Findings Methadone and buprenorphine both improve HIV viral suppression, adherence to antiretroviral therapy, and overall mortality for persons with opioid use disorder (OUD). Extended-release naltrexone has been most extensively studied in persons with HIV leaving incarcerated settings, and improves HIV viral suppression in that context. Summary Strategies that integrate MOUD and HIV treatment are crucial to optimize viral suppression. The differing pharmacokinetic and delivery characteristics of these MOUD offer diverse options. Given the chronic and relapsing nature of both HIV and OUD, long-term approaches are required.

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Effects of CYP3A4 Variants on Methadone Metabolism In Vitro

Wang,

Zhang,

et al. 2024

Biomedical Chromatography

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In hepatic drug metabolism, cytochrome P450 (CYP450) enzymes, particularly CYP3A4, catalyze the majority of drug biotransformations, accounting for over 50% of the CYP450 family's metabolic capacity. This study aimed to assess the catalytic efficiency of 22 CYP3A4 allelic variants on the in vitro oxidative metabolism of methadone. We utilized a baculovirus‐insect cell expression system to produce recombinant CYP3A4 variants and subsequently assessed their catalytic activity in the N‐demethylation of methadone. Of the 23 tested CYP3A4 allelic variants, CYP3A4*1 represents the wild type. Compared with CYP3A4*1, 12 variants displayed significantly lower intrinsic clearance of methadone, while 3 variants showed increased intrinsic clearance of methadone. Additionally, six variants demonstrated no significant difference in intrinsic clearance of methadone compared to CYP3A4*1, and one variant showed no detectable expression. Our evaluation of the enzymatic activity of CYP3A4 gene polymorphisms on methadone can aid in the personalized clinical use of methadone and facilitate the investigation into the relationship between genetic variations and clinical phenotypes.

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Methadone Metabolism and Drug-Drug Interactions: In Vitro and In Vivo Literature Review

Cited by 48 publications

References 88 publications

Inhibitory effect of isavuconazole, ketoconazole, and voriconazole on the pharmacokinetics of methadone in vivo and in vitro

Inhibitory effect of isavuconazole, ketoconazole, and voriconazole on the pharmacokinetics of methadone in vivo and in vitro

Medications for Treatment of Opioid Use Disorder among Persons Living with HIV

Effects of CYP3A4 Variants on Methadone Metabolism In Vitro

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