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Enantiomeric metabolic interactions and stereoselective human methadone metabolism.

Publication ,  Journal Article
Totah, RA; Allen, KE; Sheffels, P; Whittington, D; Kharasch, ED
Published in: J Pharmacol Exp Ther
April 2007

Methadone is administered as a racemate, although opioid activity resides in the R-enantiomer. Methadone disposition is stereoselective, with considerable unexplained variability in clearance and plasma R/S ratios. N-Demethylation of methadone in vitro is predominantly mediated by cytochrome P450 CYP3A4 and CYP2B6 and somewhat by CYP2C19. This investigation evaluated stereoselectivity, models, and kinetic parameters for methadone N-demethylation by recombinant CYP2B6, CYP3A4, and CYP2C19, and the potential for interactions between enantiomers during racemate metabolism. CYP2B6 metabolism was stereoselective. CYP2C19 was less active, and stereoselectivity was opposite that for CYP2B6. CYP3A4 was not stereoselective. With all three isoforms, enantiomer N-dealkylation rates in the racemate were lower than those of (R)-(6-dimethyamino-4,4-diphenyl-heptan-3-one) hydrochloride (R-methadone) or (S)-(6-dimethyamino-4,4-diphenyl-heptan-3-one) hydrochloride (S-methadone) alone, suggesting an enantiomeric interaction and mutual metabolic inhibition. For CYP2B6, the interaction between enantiomers was stereoselective, with S-methadone as a more potent inhibitor of R-methadone N-demethylation than R-of S-methadone. In contrast, enantiomer interactions were not stereoselective with CYP2C19 or CYP3A4. For all three cytochromes P450, methadone N-demethylation was best described by two-site enzyme models with competitive inhibition. There were minor model differences between cytochromes P450 to account for stereoselectivity of metabolism and enantiomeric interactions. Changes in plasma R/S methadone ratios observed after rifampin or troleandomycin pretreatment in humans in vivo were successfully predicted by CYP2B6- but not CYP3A4-catalyzed methadone N-demethylation. CYP2B6 is a predominant catalyst of stereoselective methadone metabolism in vitro. In vivo, CYP2B6 may be a major determinant of methadone metabolism and disposition, and CYP2B6 activity and stereoselective metabolic interactions may confer variability in methadone disposition.

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Published In

J Pharmacol Exp Ther

DOI

ISSN

0022-3565

Publication Date

April 2007

Volume

321

Issue

1

Start / End Page

389 / 399

Location

United States

Related Subject Headings

  • Thiobarbituric Acid Reactive Substances
  • Superoxides
  • Sulfonamides
  • Stereoisomerism
  • Rifampin
  • Pharmacology & Pharmacy
  • Oxidoreductases, N-Demethylating
  • Nitrobenzenes
  • Narcotics
  • Mixed Function Oxygenases
 

Citation

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Totah, R. A., Allen, K. E., Sheffels, P., Whittington, D., & Kharasch, E. D. (2007). Enantiomeric metabolic interactions and stereoselective human methadone metabolism. J Pharmacol Exp Ther, 321(1), 389–399. https://doi.org/10.1124/jpet.106.117580
Totah, Rheem A., Kyle E. Allen, Pamela Sheffels, Dale Whittington, and Evan D. Kharasch. “Enantiomeric metabolic interactions and stereoselective human methadone metabolism.J Pharmacol Exp Ther 321, no. 1 (April 2007): 389–99. https://doi.org/10.1124/jpet.106.117580.
Totah RA, Allen KE, Sheffels P, Whittington D, Kharasch ED. Enantiomeric metabolic interactions and stereoselective human methadone metabolism. J Pharmacol Exp Ther. 2007 Apr;321(1):389–99.
Totah, Rheem A., et al. “Enantiomeric metabolic interactions and stereoselective human methadone metabolism.J Pharmacol Exp Ther, vol. 321, no. 1, Apr. 2007, pp. 389–99. Pubmed, doi:10.1124/jpet.106.117580.
Totah RA, Allen KE, Sheffels P, Whittington D, Kharasch ED. Enantiomeric metabolic interactions and stereoselective human methadone metabolism. J Pharmacol Exp Ther. 2007 Apr;321(1):389–399.

Published In

J Pharmacol Exp Ther

DOI

ISSN

0022-3565

Publication Date

April 2007

Volume

321

Issue

1

Start / End Page

389 / 399

Location

United States

Related Subject Headings

  • Thiobarbituric Acid Reactive Substances
  • Superoxides
  • Sulfonamides
  • Stereoisomerism
  • Rifampin
  • Pharmacology & Pharmacy
  • Oxidoreductases, N-Demethylating
  • Nitrobenzenes
  • Narcotics
  • Mixed Function Oxygenases