Skip to main content
Journal cover image

Methadone N-demethylation by the common CYP2B6 allelic variant CYP2B6.6.

Publication ,  Journal Article
Gadel, S; Crafford, A; Regina, K; Kharasch, ED
Published in: Drug Metab Dispos
April 2013

The long-acting opioid methadone displays considerable unexplained interindividual pharmacokinetic variability. Methadone metabolism clinically occurs primarily by N-demethylation to 2-ethyl-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), catalyzed predominantly by CYP2B6. Retrospective studies suggest that the common allele variant CYP2B6*6 may influence methadone plasma concentrations. The catalytic activity of CYP2B6.6, encoded by CYP2B6*6, is highly substrate-dependent. This investigation compared methadone N-demethylation by CYP2B6.6 with that by wild-type CYP2B6.1. Methadone enantiomer and racemate N-demethylation by recombinant-expressed CYP2B6.6 and CYP2B6.1 was determined. At substrate concentrations (0.25-2 µM) approximating plasma concentrations occurring clinically, rates of methadone enantiomer N-demethylation by CYP2B6.6, incubated individually or as the racemate, were one-third to one-fourth those by CYP2B6.1. For methadone individual enantiomers and metabolism by CYP2B6.6 compared with CYP2B6.1, Vmax was diminished, Ks was greater and the in vitro intrinsic clearance was diminished 5- to 6-fold. The intrinsic clearance for R- and S-EDDP formation from racemic methadone was diminished approximately 6-fold and 3-fold for R- and S-methadone, respectively. Both CYP2B6.6 and CYP2B6.1 showed similar stereoselectivity (S>R-methadone). Human liver microsomes with diminished CYP2B6 content due to a CYP2B6*6 allele had lower rates of methadone N-demethylation. Results show that methadone N-demethylation catalyzed by CYP2B6.6, the CYP2B6 variant encoded by the CYP2B6*6 polymorphism, is catalytically deficient compared with wild-type CYP2B6.1. Diminished methadone N-demethylation by CYP2B6.6 may provide a mechanistic explanation for clinical observations of altered methadone disposition in individuals carrying the CYP2B6*6 polymorphism.

Duke Scholars

Published In

Drug Metab Dispos

DOI

EISSN

1521-009X

Publication Date

April 2013

Volume

41

Issue

4

Start / End Page

709 / 713

Location

United States

Related Subject Headings

  • Stereoisomerism
  • Pharmacology & Pharmacy
  • Oxidoreductases, N-Demethylating
  • Microsomes, Liver
  • Methadone
  • Isoenzymes
  • In Vitro Techniques
  • Humans
  • Cytochrome P-450 CYP2B6
  • Aryl Hydrocarbon Hydroxylases
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Gadel, S., Crafford, A., Regina, K., & Kharasch, E. D. (2013). Methadone N-demethylation by the common CYP2B6 allelic variant CYP2B6.6. Drug Metab Dispos, 41(4), 709–713. https://doi.org/10.1124/dmd.112.050625
Gadel, Sarah, Amanda Crafford, Karen Regina, and Evan D. Kharasch. “Methadone N-demethylation by the common CYP2B6 allelic variant CYP2B6.6.Drug Metab Dispos 41, no. 4 (April 2013): 709–13. https://doi.org/10.1124/dmd.112.050625.
Gadel S, Crafford A, Regina K, Kharasch ED. Methadone N-demethylation by the common CYP2B6 allelic variant CYP2B6.6. Drug Metab Dispos. 2013 Apr;41(4):709–13.
Gadel, Sarah, et al. “Methadone N-demethylation by the common CYP2B6 allelic variant CYP2B6.6.Drug Metab Dispos, vol. 41, no. 4, Apr. 2013, pp. 709–13. Pubmed, doi:10.1124/dmd.112.050625.
Gadel S, Crafford A, Regina K, Kharasch ED. Methadone N-demethylation by the common CYP2B6 allelic variant CYP2B6.6. Drug Metab Dispos. 2013 Apr;41(4):709–713.
Journal cover image

Published In

Drug Metab Dispos

DOI

EISSN

1521-009X

Publication Date

April 2013

Volume

41

Issue

4

Start / End Page

709 / 713

Location

United States

Related Subject Headings

  • Stereoisomerism
  • Pharmacology & Pharmacy
  • Oxidoreductases, N-Demethylating
  • Microsomes, Liver
  • Methadone
  • Isoenzymes
  • In Vitro Techniques
  • Humans
  • Cytochrome P-450 CYP2B6
  • Aryl Hydrocarbon Hydroxylases