Effect of gender, sex hormones, time variables and physiological urinary pH on apparent CYP2D6 activity as assessed by metabolic ratios of marker substrates

The effects of gender, time variables, menstrual cycle phases, plasma sex h ormone concentrations and physiologic urinary pH on CYP2D6 phenotyping were studied using two widely employed CYP2D6 probe drugs, namely dextromethorp han and metoprolol. Phenotyping on a single occasion of 150 young, healthy, drug-free women and men revealed that the dextromethorphan: dextrorphan me tabolic ratio (MR) was significantly lower (P < 0.0001) in 56 female extens ive metabolizers (0.008 +/- 0.021) compared to 86 male extensive metabolize rs (0.020 +/- 0.040). Urinary pH was a significant predictor of dextrometho rphan: dextrorphan MRs in men and women (P < 0.001). Once-a-month phenotypi ng with dextromethorphan of 12 healthy young men (eight extensive metaboliz ers and four poor metabolizers) over a 1-year period, as well as every-othe r-day phenotyping with dextromethorphan of healthy, pre-menopausal women (1 0 extensive metabolizers and 2 poor metabolizers) during a complete menstru al cycle, did not follow a particular pattern and showed similar intrasubje ct variability ranging from 24.1% to 74.5% (mean 50.9%) in men and from 20. 5% to 96.2% (mean 52.0%) in women, independent of the CYP2D6 phenotype (P = 0.342). Using metoprolol as a probe drug, considerable intrasubject variab ility (38.6 +/- 12.0%) but no correlation between metoprolol: alpha-hydroxy metoprolol MRs and pre-ovulatory, ovulatory and luteal phases (mean +/- SD metoprolol: a-hydroxymetoprolol MRs: 1.086 +/- 1.137 pre-ovulatory; 1.159 /- 1.158 ovulatory and 1.002 +/- 1.405 luteal phase; P > 0.9) or 17 beta-oe stradiol, progesterone or testosterone plasma concentrations was observed. There was a significant inverse relationship between physiologic urinary pH and sequential dextromethorphan: dextrorphan MRs as well as metoprolol: al pha-hydroxymetoprolol MRs in men and women, with metabolic ratios varying u p to six-fold with metoprolol and up to 20-fold with dextromethorphan (ANCO VA P < 0.001). We conclude that apparent CYP2D6 activity is highly variable , independent of menstrual cycle phases, sex hormones, time variables or ph enotype. Up to 80% of the observed variability can be explained by variatio ns of urinary pH within the physiological range. An apparent phenotype shif t as a result of variations in urinary pH may be observed in individuals wh o have metabolic ratios close to the population antimode. Pharmacogenetics 10:425-438 (C) 2000 Lippincott Williams & Wilkins.