QUANTIFICATION OF INTRAINDIVIDUAL VARIABILITY AND THE INFLUENCE OF MENSTRUAL-CYCLE PHASE ON CYP2D6 ACTIVITY AS MEASURED BY DEXTROMETHORPHANPHENOTYPING

Intraindividual variability and the effects of menstrual cycle phase o n CYP2D6 activity were evaluated by dextromethorphan phenotyping in 20 Caucasian normal volunteers. Dextromethorphan 30 mg was administered to 10 men every 14 days for 3 months, and to 10 premenopausal women du ring the mid-follicular and mid-luteal phases of each menstrual cycle for three complete cycles. Urinary dextromethorphan/dextrorphan molar ratios were obtained after an overnight urine collection, Ten women an d nine men were extensive metabolizer phenotypes, and one man was a po or metabolizer phenotype (confirmed by genotyping). There was no diffe rence in dextromethorphan metabolic ratios between the mid-follicular (mean +/- SD: 0.00728 +/- 0.00717) and mid-luteal (0.00745 +/- 0.00815 ) phases of the menstrual cycle (P = 0.88). Also, no significant diffe rence was found in the intraindividual variability of the metabolic ra tios between the two phases (P = 0.80). No statistically significant s ex difference in CYP2D6 activity was found between men (0.00537 +/- 0. 00431) and women (0.00737 +/- 0.00983) extensive metabolizers (P = 0.8 4). For all individuals, intraindividual variability in dextromethorph an ratios ranged from 12.1-136.6% with a median of 36.7%. Because horm onal fluctuations within the mid-follicular and mid-luteal phases of t he menstrual cycle do not appear to affect CYP2D6 activity, pharmacoki netic or clinical investigations of CYP2D6 substrate activity may not require menstrual cycle phase stratification. Because baseline metabol ic ratios may fluctuate an average of 37%, repeat baseline and treatme nt phenotyping assessments should be obtained for accurate determinati on of a given drug's effect on CYP2D6 activity when measured by dextro methorphan, Pharmacogenetics 8:403-410 (C) 1998 Lippincott Williams & Wilkins.