title: Limitations of dextromethorphan N-demethylation as a measure of CYP3A activity.
abstract: We evaluated the utility of the 3-methoxymorphinan/dextromethorphan (3MM/DM) urinary ratio to reflect baseline CYP3A activity, and its ability to discriminate moderate CYP3A inhibition during fluvoxamine therapy. For 4 months, oral dextromethorphan 30 mg and intravenous midazolam 0.025 mg/kg were administered to nine men every 14 days, and to 10 premenopausal women during the follicular and luteal phases of their menstrual cycles. Phenotyping during the first 3 months or cycles established baseline CYP3A activity. During the fourth month, individuals were given fluvoxamine 150 mg/day. CYP3A activity was expressed as both the urinary 3MM/DM molar ratio and midazolam plasma clearance (MDZ CL). 3MM/DM ratios were independent of dextromethorphan CYP2D6 phenotype (r = 0.13, P = 0.6). Intraindividual variability in baseline CYP3A activity (median, 25-75th percentile), as determined by coefficients 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 the 3MM/DM ratios was -50.0% (-105.6-6.0%; P = 0.7), and median percentage change in MDZ CL was -33.7% (-27.0-39.3%; P < 0.0001). Only MDZ CL consistently indicated moderate inhibition of hepatic CYP3A activity. In addition, there was a lack of correlation between the magnitudes of fluvoxamine-induced change in 3MM/DM and MDZ CL (r = 0.41, P = 0.1). The large intraindividual variability of the 3MM/DM urinary ratio, as well as the inability to discriminate moderate CYP3A inhibition, makes this a suboptimal method for accurately assessing CYP3A activity.
authors.affiliation: Clinical Pharmacology Research Centre, Bassett Healthcare, Cooperstown, New York, USA. akashuba@unc.edu
authors.forename: A D
authors.initials: AD
authors.lastname: Kashuba
authors.forename: A N
authors.initials: AN
authors.lastname: Nafziger
authors.forename: G L
authors.initials: GL
authors.lastname: Kearns
authors.forename: J S
authors.initials: JS
authors.lastname: Leeder
authors.forename: R
authors.initials: R
authors.lastname: Gotschall
authors.forename: A
authors.initials: A
authors.lastname: Gaedigk
authors.forename: J S
authors.initials: JS
authors.lastname: Bertino
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003915:Dextromethorphan / Q000031:analogs & derivatives / Q000378:metabolism* / Q000652:urine; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008745:Methylation; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010641:Phenotype
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; C028657:3-methoxymorphinan; D003915:Dextromethorphan; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating