Dextromethorphan CYP2D6 substrate

Preliminary results from a study our group was conducting of dextromethorphan (a CYP2D6 substrate) metabolism in four ethnic groups in Southern California appear to support some of these assumptions (Mendoza et al., submitted). The frequency distribution of PMs in the Mexican American study sample was 2.8%, midway between that for Asians and whites. The Mexican American cohort exhibited the fastest rate of dextromethorphan metab-... 

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. ... 

There is a wide choice of dmgs that are substrates for CYP2D6, but sparteine, debrisoquine, desipramine, dextromethorphan, and metoprolol have been used most frequently, both in vitro and in vivo. One advantage for in vivo drug-drug interaction studies is that most of the substrates were identified in the clinic rather than by the use of a battery of in vitro methods. 

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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