Methadone is a long-acting opioid with considerable unexplained interindividual variability in clearance. Cytochrome P450 2B6 (CYP2B6) mediates clinical methadone clearance and metabolic inactivation via N-demethylation to 2-ethyl-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP). Retrospective studies suggest that individuals with the CYP2B6*6 allelic variant have higher methadone plasma concentrations. Catalytic activities of CYP2B6 variants are highly substrate- and expression-system dependent. This investigation evaluated methadone N-demethylation by expressed human CYP2B6 allelic variants in an insect cell coexpression system containing P450 reductase. Additionally, the influence of coexpressing cytochrome b5, whose role in metabolism can be inhibitory or stimulatory depending on the P450 isoform and substrate, on methadone metabolism, was evaluated. EDDP formation from therapeutic (0.25-1 μM) R- and S-methadone concentrations was CYP2B6.4 ≥ CYP2B6.1 ≥ CYP2B6.5 >> CYP2B6.9 ≈ CYP2B6.6, and undetectable from CYP2B6.18. Coexpression of b5 had small and variant-specific effects at therapeutic methadone concentrations but at higher concentrations stimulated EDDP formation by CYP2B6.1, CYP2B6.4, CYP2B6.5, and CYP2B6.9 but not CYP2B6.6. In vitro intrinsic clearances were generally CYP2B6.4 ≥ CYP2B6.1 > CYP2B6.5 > CYP2B6.9 ≥ CYP2B6.6. Stereoselective methadone metabolism (S>R) was maintained with all CYP2B6 variants. These results show that methadone N-demethylation by CYP2B6.4 is greater compared with CYP2B6.1, whereas CYP2B6.9 and CYP2B6.6 (which both contain the 516G>T, Q172H polymorphism), are catalytically deficient. The presence or absence of b5 in expression systems may explain previously reported disparate catalytic activities of CYP2B6 variants for specific substrates. Differences in methadone metabolism by CYP2B6 allelic variants provide a mechanistic understanding of pharmacogenetic variability in clinical methadone metabolism and clearance.
Download full-text PDF |
Source |
---|---|
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4468442 | PMC |
http://dx.doi.org/10.1124/dmd.115.064352 | DOI Listing |
Hum Vaccin Immunother
December 2025
School of Public Health, Shanxi Medical University, Taiyuan, Shanxi, China.
ClinicalTrials.gov (NCT03962816).https://clinicaltrials.
View Article and Find Full Text PDFDrug Alcohol Depend
February 2025
British Columbia Centre on Substance Use, 1045 Howe St Suite 400, Vancouver, British Columbia V6Z 2A9, Canada; Interdepartmental Division of Addiction Medicine, St. Paul's Hospital, 1081 Burrard Street, Vancouver, British Columbia, V6Z 1Y6.
Background: People exposed to fentanyl may report that the dose of methadone in the commonly accepted therapeutic range feels too low. We examined self-reported methadone dose adequacy.
Methods: We conducted a retrospective cohort study of individuals prescribed methadone at a dose of at least 60mg daily using data from three community-recruited prospective cohort studies of people who use drugs in Vancouver, Canada from December 2016 through March 2020.
Sci Rep
January 2025
Golestan Research Center of Gastroentrology and Hepatology & Stem Cell Research Center, Golestan University of Medical Sciences, Gorgan, Iran.
Children are highly sensitive to toxins which can damage their organs and lead to death. Investigating the main causes of intoxication could reduce mortality and morbidity in children. In this cross-sectional study, the documents of all poisoned patients (214 cases) admitted to the emergency department of Taleghani children`s Hospital between April 2020 and 2023 were investigated.
View Article and Find Full Text PDFFront Med (Lausanne)
December 2024
Metabolic Disease Research Center, Qazvin University of Medical Sciences, Qazvin, Qazvin, Iran.
Introduction: This study systematically examines the effects of chronic oral methadone use on the glomerular filtration rate (GFR) in patients participating in methadone maintenance therapy (MMT) in Qazvin City, Iran. Methadone, a synthetic -opioid receptor agonist, is predominantly utilized for the management of opioid dependence and pain relief; however, there is growing concern regarding its potential nephrotoxic effects.
Methods: An observational cross-sectional study was executed involving 150 participants who had been on methadone syrup for a minimum duration of 2 years.
Pharmacol Res Perspect
February 2025
School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Data addressing safety concerns related to potential drug interactions between cannabis-derived products and pharmaceutical medications in the pediatric population are lacking. In this study, we retrieved case reports through a published literature search using PubMed and spontaneous reporting data using the Food and Drug Administration's Adverse Event Reporting System (FAERS) to identify potential cannabis- and cannabinoid-drug interactions in individuals younger than 18 years old. To evaluate the published case reports, we used the Drug Interaction Probability Scale (DIPS), a 10-item questionnaire designed to discern the causal relationship between a potential drug interaction and adverse drug reactions (ADRs).
View Article and Find Full Text PDFEnter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!