Role of Cytochrome P4502B6 in Methadone Metabolism and Clearance.

J Clin Pharmacol. 2013 Jan 7; 1-9
Kharasch ED, Stubbert K

Methadone N-demethylation in vitro is catalyzed by hepatic cytochrome P4502B6 (CYP2B6) and CYP3A4, but clinical disposition is often attributed to CYP3A4. This investigation tested the hypothesis that CYP2B6 is a prominent CYP isoform responsible for clinical methadone N-demethylation and clearance, using the in vivo mechanism-based CYP2B6 inhibitor ticlopidine, given orally for 4 days. A preliminary clinical investigation with the CYP3A4/5 substrate probe alfentanil established that ticlopidine did not inhibit intestinal or hepatic CYP3A4/5. Subjects received intravenous plus oral (deuterium-labeled) racemic methadone before and after ticlopidine. Ticlopidine significantly and stereoselectively (S?>?R) inhibited methadone N-demethylation, decreasing plasma metabolite/methadone area under the curve ratios and metabolite formation clearances. Ticlopidine also significantly increased the dose-adjusted plasma area under the curve for R- and S-methadone by 20% and 60%, respectively, after both intravenous and oral dosing. CYP2B6 inhibition reduces methadone N-demethylation and clearance, and alters methadone concentrations, demonstrating an important role for CYP2B6 in clinical methadone disposition.
HubMed – Methadone

Bilateral Acute Necrosis of the Globi Pallidi and Rhabdomyolysis Due to Combined Methadone and Benzodiazepine Toxicity.

Am J Forensic Med Pathol. 2013 Jan 28;
Corliss RF, Mandal R, Soriano BJ

ABSTRACT: Methadone continues to be a widely used maintenance therapy for opiate dependence. However, methadone-related deaths have been reported frequently for over 4 decades now. Anoxic brain injury with pulmonary edema secondary to respiratory depression is the recognized mechanism of methadone death, although pathological intracranial findings are rarely described in methadone deaths. A selective area of brain injury has never been reported with methadone use. We present a case of a 23-year-old man who had acute necrosis of the bilateral globi pallidi in the brain and systemic rhabdomyolysis after ingesting methadone and nasally insufflating alprazolam. We also present a review of the literature on deaths following opioid use and associated brain injury.
HubMed – Methadone

QT interval and antidepressant use: a cross sectional study of electronic health records.

BMJ. 2013; 346: f288
Castro VM, Clements CC, Murphy SN, Gainer VS, Fava M, Weilburg JB, Erb JL, Churchill SE, Kohane IS, Iosifescu DV, Smoller JW, Perlis RH

To quantify the impact of citalopram and other selective serotonin reuptake inhibitors on corrected QT interval (QTc), a marker of risk for ventricular arrhythmia, in a large and diverse clinical population.A cross sectional study using electrocardiographic, prescribing, and clinical data from electronic health records to explore the relation between antidepressant dose and QTc. Methadone, an opioid known to prolong QT, was included to demonstrate assay sensitivity.A large New England healthcare system comprising two academic medical centres and outpatient clinics.38?397 adult patients with an electrocardiogram recorded after prescription of antidepressant or methadone between February 1990 and August 2011.Relation between antidepressant dose and QTc interval in linear regression, adjusting for potential clinical and demographic confounding variables. For a subset of patients, change in QTc after drug dose was also examined.Dose-response association with QTc prolongation was identified for citalopram (adjusted beta 0.10 (SE 0.04), P<0.01), escitalopram (adjusted beta 0.58 (0.15), P<0.001), and amitriptyline (adjusted beta 0.11 (0.03), P<0.001), but not for other antidepressants examined. An association with QTc shortening was identified for bupropion (adjusted beta 0.02 (0.01) P<0.05). Within-subject paired observations supported the QTc prolonging effect of citalopram (10 mg to 20 mg, mean QTc increase 7.8 (SE 3.6) ms, adjusted P<0.05; and 20 mg to 40 mg, mean QTc increase 10.3 (4.0) ms, adjusted P<0.01).This study confirmed a modest prolongation of QT interval with citalopram, and identified additional antidepressants with similar observed risk. Pharmacovigilance studies using electronic health record data may be a useful method of identifying potential risk associated with treatments. HubMed – Methadone

More Methadone Clinics Information…

Comments are closed.