Limitations of dextromethorphan N-demethylation as a measure of CYP3A activity

We evaluated the utility of the 3-methoxymorphinan/dextromethorphan (3MM/DM ) urinary ratio to reflect baseline CYP3A activity, and its ability to disc riminate moderate CYP3A inhibition during fluvoxamine therapy. For 4 months , oral dextromethorphan 30 mg and intravenous midazolam 0.025 mg/kg were ad ministered to nine men every 14 days, and to 10 premenopausal women during the follicular and luteal phases of their menstrual cycles. Phenotyping dur ing the first 3 months or cycles established baseline CYP3A activity. Durin g the fourth month, individuals were given fluvoxamine 150 mg/day. CYP3A ac tivity was expressed as both the urinary 3MM/DM molar ratio and midazolam p lasma clearance (MDZ CL), 3MM/DM ratios were independent of dextromethorpha n CYP2D6 phenotype (r = 0.13, P = 0.6). Intraindividual variability in base line CYP3A activity (median, 25-75th percentile), as determined by coeffici ents of variation, was 48.3% (36.8-68.8%) for 3MM/DM and 10.3% (8.3-11.8%) for MDZ CL. No significant correlation between 3MM/DM and MDZ CL either at baseline (r = -0.22, P = 0.4) or during fluvoxamine therapy (r = -0.15, P = 0.6) was noted. With fluvoxamine 150 mg/day median percentage change in th e 3MM/DM ratios was -50.0% (-105.6-6.0%; P = 0.7), and median percentage ch ange in MDZ CL was -33.7% (-27.0 -39.3%; P < 0.0001). Only MDZ CL consisten tly indicated moderate inhibition of hepatic CYP3A activity. In addition, t here was a lack of correlation between the magnitudes of fluvoxamine-induce d change in 3MM/DM and MDZ CL (r = 0.41, P = 0.1), The large intraindividua l variability of the 3MM/DM urinary ratio, as well as the inability to disc riminate moderate CYP3A inhibition, makes this a suboptimal method for accu rately assessing CYP3A activity. Pharmacogenetics 9:453-462 (C) 1999 Lippin cott Williams & Wilkins.