Role of cytochrome P4502B6 in methadone metabolism and clearance

J Clin Pharmacol. 2013 Mar;53(3):305-13. doi: 10.1002/jcph.1. Epub 2013 Jan 7.


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.

Publication types

  • Controlled Clinical Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Administration, Intravenous
  • Administration, Oral
  • Adult
  • Analgesics, Opioid / administration & dosage
  • Analgesics, Opioid / blood
  • Analgesics, Opioid / pharmacokinetics*
  • Analgesics, Opioid / urine
  • Aryl Hydrocarbon Hydroxylases / antagonists & inhibitors
  • Aryl Hydrocarbon Hydroxylases / metabolism*
  • Cytochrome P-450 CYP2B6
  • Enzyme Inhibitors / pharmacology
  • Female
  • Humans
  • Male
  • Methadone / administration & dosage
  • Methadone / blood
  • Methadone / pharmacokinetics*
  • Methadone / urine
  • Middle Aged
  • Oxidoreductases, N-Demethylating / antagonists & inhibitors
  • Oxidoreductases, N-Demethylating / metabolism*
  • Ticlopidine / pharmacology
  • Young Adult


  • Analgesics, Opioid
  • Enzyme Inhibitors
  • Aryl Hydrocarbon Hydroxylases
  • CYP2B6 protein, human
  • Cytochrome P-450 CYP2B6
  • Oxidoreductases, N-Demethylating
  • Ticlopidine
  • Methadone