Metabolism of dextromethorphan

Dextromethorphan is known to interact with quini-dine and terbinafine. In both cases, there is a reduction in the metabolism of dextromethorphan by the liver. Terbinafine is a drug used to treat fungal infections. Quinidine is used for the treatment of malarial infections and heart rhythm problems. There has been a case report of a drug interaction between the use of fluoxetine (Prozac) and dextromethorphan. Fluoxetine is an antidepressant in the class of drugs called serotonin reuptake inhibitors. 

Kerry NL, Somogyi A A, Mikus G, et al. Primary and secondary oxidative metabolism of dextromethorphan. In vitro studies with female Sprague-Dawley and Dark Agouti rat liver microsomes. Biochem Pharmacol 1993 45 833-839. 

Jacqz-Aigrain E, Funck-Brentano C, Crested T. CYP2D6- and CYP3A-dependent metabolism of dextromethorphan in humans. Pharmacogenetics 1993 3 197-204. 

Schmider J, Greenblatt DJ, Fogelman SM, et al. Metabolism of dextromethorphan in vitro involvement of cytochromes P450 2D6 and 3A3/4, with a possible role of 2E1. Biopharm Drug Dispos 1997 18 227-240. 

Kerry NL, Somogyi AA, Bochner F, et al. The role of CYP2D6 in primary and secondary oxidative metabolism of dextromethorphan in vitro studies using human liver microsomes. Br J Clin Pharmacol 1994 38 243-248. 

The effects of quinidine sulfate, 50 mg orally, an inhibitor of cytochrome CYP2D6, on the metabolism of dextromethorphan 50 mg have been studied in seven healthy volunteers in a randomized, double-blind, crossover, placebo-controlled study (24). Quinidine suppressed the conversion of dextromethorphan to dextrorphan in extensive metabolizers to the extent seen in poor metabolizers. The increased concentrations of dextromethorphan increased subjective and objective pain thresholds by 35 and 45 % respectively. This result suggests that debriso-quine/sparteine-type polymorphisms account for important differences in the effect of dextromethorphan and the balance between the analgesic effect of dextromethorphan and the hallucinogenic effect of dextrorphan. Concomitant use of quinidine or other inhibitors of CYP2D6 could... 

In 31 healthy men and women (mean age 28 years) the ability of four SSRIs (fluoxetine, fluvoxamine, paroxetine, and sertraline) to inhibit CYP2D6 activity was assessed in vivo, as judged by the dextromethorphan test (63). All were extensive metabolizers of dextromethorphan. After 8 days treatment at therapeutic doses, four of eight paroxetine-treated and five of eight fluoxetine-treated subjects had become poor metabolizers, presumably because of the inhibitory effect of the two SSRIs... 

Dextromethorphan Some SSRIs inhibit the metabolism of dextromethorphan visual hallucinations have occurred it may cause serotonin syndrome... 

Figure 34-40 Metabolism of dextromethorphan. Values in parenthesis are percent of dose excreted in urine.

Eap, C.B. Guentert, T.W. Schaublin-Loidl, M. Stabl, M. Koeb, L. Powell, K. Baumann, P. Plasma levels of the enantiomers of thioridazine, thioridazine 2-sulfoxide, thioridazine 2-sulfone, and thioridazine 5-sulfoxide in poor and extensive metabolizers of dextromethorphan and mephenytoin. Clin. Pharmacol. Ther. 1996, 59, 322-331. 

Aripiprazole 10 to 30 mg daily had no significant effects on the metabolism of dextromethorphan (CYP2D6 and CYP3A4 substrate), warfarin (CYP2C9 substrate) and omeprazole (CYP2C19 substrate). Aripiprazole is not expected to affect CYPl A2-mediated metabolism. The manufacturers therefore conclude that aripiprazole is unlikely to have clinically significant interactions with drugs that are substrates for these isoenzymes. ... 

Two fatal cases of hyperpyrexia and coma (symptoms similar to the serotonin syndrome) have occurred in patients taking phenelzine with dextromethorphan (in overdosage in one case). Three other serious but non-fatal reactions occurred in patients taking dextromethorphan with isocarboxazid or phenelzine. MAOIs should not be used with dextromethorphan. Mo-clobemide inhibits the metabolism of dextromethorphan, and isolated cases of severe CNS reactions have occurred with the combination, which is also contraindicated. 

Moclobemide appears to inhibit the metabolism of dextromethorphan by the cytochrome P450 isoenzyme CYP2D6, and the combination may also cause adverse CNS effects. 

Bupropion may reduce the metabolism of dextromethorphan in some patients. 

A study in 21 subjects who were quitting smoking and were CYP2D6 extensive metabolisers, found that 6 of 13 subjects who received bupropion 150 mg once daily for 3 days and then twice daily for 14 days had metabolic ratios of dextromethorphan 30 mg similar to those seen in poor metabolisers the metabolism of dextromethorphan to dextrorphan was substantially reduced. No such change was seen in the 8 subjects who received placebo. It has been suggested that care should be taken when ini-... 

Ginkgo biloba does not affect the metabolism of dextromethorphan. 

Quinidine inhibits the oxidative metabolism of dextromethorphan by the eytochrome P450 isoenzyme CYP2D6 to dextrorphan, effeetively making extensive metabolisers of CYP2D6 into the poor metaboliser phenotype, see Genetic factors in drug metabolism , (p.4), for further discussion of metaboliser phenotypes. 

Psychiatric A 60-year-old woman developed a psychosis after taking dextromethorphan at more than the recommended over-the-counter dosage, propoxyphene, and hydrocodone [71 ]. She developed religious and paranoid delusions, olfactory and visual hallucinations, and agitation. Propoxyphene may have slowed the metabolism of dextromethorphan, resulting in intoxication. 

The opioid derivatives most commonly used as antitussives are dextromethorphan, codeine, levopropoxyphene, and noscapine (levopropoxyphene and noscapine are not available in the USA). They should be used with caution in patients taking monoamine oxidase inhibitors (see Table 31-5). Antitussive preparations usually also contain expectorants to thin and liquefy respiratory secretions. Importantly, due to increasing reports of death in young children taking dextromethorphan in formulations of over-the-counter "cold/cough" medications, its use in children less than 6 years of age has been banned by the FDA. Moreover, due to variations in the metabolism of codeine, its use for any purpose in young children is being reconsidered. 

Pope LE, Khalil MH, Berg JE, et al. Pharmacokinetics of dextromethorphan after single or multiple dosing in combination with quinidine in extensive and poor metabolizers. J Clin Pharmacol 2004 44 1132-1142. 

Hou ZY, Pickle LW, Meyer PS, et al. Salivary analysis of determination of dextromethorphan metabolic phenotype. Clin Pharmacol Ther 1991 49 410419. 

Evans WE, Relling MV. Concordance of P450 2D6 (debrisoquine hydroxylase) phenotype and genotype inability of dextromethorphan metabolic ratio to discriminate reliably heterozygous and homozygous extensive metabolizers. Pharmacogenetics 1991 1 143-148. 

Funck-Brentano C, Thomas G, Jacqz-Algrain E, et al. Polymorphism of dextromethorphan metabolism relationships between phenotype, genotype and response to the administration of encainide in humans. J Pharmacol Exp Ther 1992 263 780-786. 

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. 

Hartter S, Dingemanse J, Baier D, Ziegler G, Hiemke C. Inhibition of dextromethorphan metabolism by moclobemide. Psychopharmacology (Berl) 1998 135(l) 22-6. 

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