Dextromethorphan O-demethylation

Dayer P, Leemann T, Stribemi R. Dextromethorphan O-demethylation in liver microsomes as a prototype reaction to monitor cytochrome P-450 dbl activity. Clin Pharmacol Ther 1989 45 34-40. 

Kiipfer A, Schmid B, Pfaff G. Pharmacogenetics of dextromethorphan O-demethylation in man. Xenobiotica 1986 16 4214-33. 

Zimmermann T, Schlenk R, Pfaff P, et al. Prediction of phenotype for dextromethorphan O-demethylation by using polymerase chain reaction in healthy volunteers. Arzneimittelforschung 1995 45 41 13. 

Irshaid YM, Al-Hadidi HF, Latif A, et al. Dextromethorphan metabolism in Jordanians dissociation of dextromethorphan O-demethylation from debrisoquine 4-hydroxylation. Eur J Clin Metab Pharmacokinet 1996 21 301-307. 

Nelson AC, Huang W, Moody DE. Human liver microsome preparation impact on the kinetics of L-a-acetylmethadol (LAAM) N-demethylation and dextromethorphan O-demethylation. Drug Metab Disp. 2001 29 319-325. 

Whatever the precise mechanism, in vitro experiments with purified CYP2D6 indicate that the formation of MI complexes with a telltale spectroscopic signature at 456 nm may be responsible for the clinical reports of potent CYP2D6 inhibition by paroxetine (Figure 7.12), a serotonin reuptake inhibitor. The formation of a carbene complex is supported by the fact that paroxetine is metabolized by CYP2D6 via demethylenation of the methylenedioxy group to a catechol and formic acid - K, and t values of 6.6 2.7 p,M and 0.25 0.09 min , respectively, have been calculated for the paroxetine-mediated inhibition of human liver microsomal CYP2D6-dependent dextromethorphan O-demethylation-. ... 

D6 Debrisoquine 4-hydroxylation-[Pg.621]

Lack of association between glucose-6-phosphate dehydrogenase deficiency and dextromethorphan O-demethylation polymorphism. 

Yu A, Dong H, Lang D, Raining RL. 2001. Characterization of dextromethorphan O- and N-demethylation catalyzed by highly purified recombinant human cyp2d6. Drug Metab Dispos 29 1362-1365. 

Blake MJ, Gaedigk A, Pearce RE, Bomgaars LR, Christensen ML, Stowe C, James LP, Wilson JT, Kearns GL, Leeder JS. Ontogeny of dextromethorphan O- and N-demethylation in the first year of life. Clin Pharmacol Ther 2007 81(4) 510-6. 

Dextromethorphan and its O-demethylated metabolite dextrorphan (morphinans), are also low to medium affinity NMDA channel blockers. The former has been in clinical use as an antitussive for about 40 years and could therefore be considered as a very safe drug (Bern et al., 1992). 

Schmid B, Bircher J, Preisig R, et al. Polymorphic dextromethorphan metabolism co-segregation of oxidative O-demethylation with debrisoquine hydroxylation. Clin Pharmacol Ther 1985 38 618-624. 

Phenotyping The method measures dextromethorphan DM and its O-demethylated metabolite, dextror-phan DX, which is formed by CYP2D6. DM and DX, and other metabolites, are excreted in urine, mainly as glucuronide conjugates. 

Four subjects had markedly reduced O-demethylation of dextromethorphan after they had taken moclobemide 300 mg bd for 9 days (60). A-demethylation was not affected. This result supports the hypothesis that moclobemide or a metabolite reduces the activity of the cytochrome enzyme CYP2D6. The clinical implications of this particular interaction remain to be clarified. 

A. Both dextromethorphan and its o-demethylated metabolite appear to antagonize /V-methyl-D-aspartate (NMDA) glutamate receptors, which may explain anticonvulsant properties and protection against hypoxia-ischemia observed in animal models. 

Moclobemide 300 mg twice daily for 9 days markedly reduced the O-demethylation of dextromethorphan (seven 20-mg doses given every 4 hours over 2 days), in 4 healthy subjects. The manufacturer notes that isolated cases of severe CNS adverse reactions have been seen with the combination. Concurrent use of dextromethorphan may have contributed to a fatality involving the illicit use of moclobemide and ecstasy , (p.1144). 

In vitro studies using liver microsomes have shown that amiodarone inhibits the metabolism (O-demethylation) of dextromethorphan by inhibiting the cytoehrome P450 isoenzyme CYKD6 within the liver. Thus the dextromethorphan is eleared more slowly. 

Dextromethorphan is usually taken orally and is well absorbed from the gastrointestinal tract It is metabolized in the hver by various hepatic enzymes and subsequently imdergoes O-demethylation into an active metabohte dextrophan, N-demethylation, and partial conjugation with glucuronic acid and sulfate ions. One well-known metabohe catalyst involved is a specific cytochrome P450 enzyme known as 2D6, or CYP2D6. The therapeutic activity of dextromethorphan is beheved to be caused by both the drug and this metabohte. Dextromethorphan and its metabolites are excreted via kidney. 

Dextromethorphan (3-methoxy-17-methylmorphinan) is a widely used and effective non-narcotic antitussive. After oral administration, it is rapidly and extensively metabolized in humans by O- and N-demethylation to form dextrorphan and 3-methoxymorphinan a small amount of secondary metabolite, 3-hydroxymorphinan, is also formed. N-Demethylation is mediated mainly by... 

Recombinant human CYP2D6 was shown to be selective for the O-demethyla-tion of dextromethorphan at or near the K n for this cytochrome s interaction with this substrate (at a concentration of 3 pM), whereas at higher substrate concentrations CYPs of the cytochrome 2C family contributed significantly to the metabolism of the drug. Similarly, diazepam at a concentration of 100 pM was N-demethylated principally by CYPs 3A4 and 2C19. However, at the lower concentration of 20 pM, the metabolism mediated by CYP3A4 was reduced to 30% that of CYP2C19. 

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