C Lack of Gender Differences and Large Intrasubject Variability in Cytochrome P450 Activity Measured by Phenotyping with Dextromethorphan Jeannine S. McCune, PharmD, Celeste Lindley, MS, PharmD, Jodi L. Decker, PharmD, Kristin M. Williamson, PharmD, Amy M. Meadowcroft, PharmD, Donald Graff, PharmD, William T. Sawyer, MS, David K. Blough, PhD, and John A. Pieper, PharmD G ender-based differences in the pharmacokinetic disposition of medications have been recognized. 1 These differences are particularly important for the cytochrome P450 3A4 enzyme (CYP3A4), which repre - sents 28% ofthe totalamountof cytochrome P450 (CYP) within the human liver and is involved in the metabolism of 60% of medications. 2-4 CYP3A4 activ- ity is reportedly higher in women than men, based on increased clearance ofCYP3A4 substrates such as erythromycin, methylprednisolone,prednisolone, midazolam, verapamil, alfentanil, tirilazad, and cyclosporine in women. 1,5-12 In vitro data suggest that CYP3A4 activity may differ between men and women because of endogenous hor - J Clin Pharmacol 2001;41:723-731 723 From the University of Washington, Seattle (Dr. McCune, Dr. Blough); Uni - versity of North Carolina, Chapel Hill(Dr. Lindley, Dr. Graff, Dr. Pieper); Glaxo Wellcome, Inc. (Dr. Decker, Dr. Meadowcroft); and Quintiles, Inc., Research Triangle Park, North Carolina (Dr. Williamson, Mr. Sawyer). Fi - nancialsupport was provided by NIH GCRC grant RR00046 and the Women’sHealth Initiative Grant Program atthe University of North Carolina School of Medicine. Submitted for publication May 23, 2000; revised version accepted December 19, 2000. Addressfor reprints: Celeste Lindley, MS, PharmD, University of North Carolina at Chapel Hill, Division of Pharmacotherapy, CB #7360, Beard Hall, Chapel Hill, NC 27599-7360. Gender-based differences in cytochrome P450 (CYP) activity may occur due to endogenous hormonal fluctuations with the menstrual cycle, which are altered by oral contraceptives. This study assessed the average activity and within-subject variability in CYP3A4 and CYP2D6 in men, women taking Triphasil ® , and regularly menstruating women not receiving oral contraceptives. Thirty-three healthy volunteers partici- pated in this 28-day pilot study (12 women receiving Triphasil ® ) (OCs), 11 regularly menstruating women not on exogenous progesterone or estrogen (no OCs), and 10 men. CYP3A4 and CYP2D6 activities were phenotyped with dextromethorphan (DM) on study days 7, 14, 21, and 28 using urinary ratios of DM:3-methoxymorphinan (3MM)and DM:dextrorphan (DX), respectively. Serial blood concentra- tions of estrogen and progesterone and menstrual diaries were used to determine menstrual phase in both groups of women. Average urinary DM:3MM and DM:DX in the 28 ex - tensive metabolizers of CYP2D6 did not differ between the three study populations (p = 0.86 and 0.93, respectively). Post hoc power analysis indicated that more than 1000 subjects would be needed for 80% power ( α = 0.05) to detect a ±15% difference from the population mean in the urinary ratios of dextromethorphan and its metabolites 3MM and DX. Vari- ability in CYP3A4 and CYP2D6 activity,characterized by intrasubject standard deviation, also did not differ. The vary- ing doses of levonorgesteroland ethinyl estradiol in Triphasil ® , fluctuations in estrogen and progesterone, and menstrual phase did not influence CYP3A4 or CYP2D6 activ- ity. It was concluded that CYP3A4 and CYP2D6 activity and intrasubject variability were not different in the three study populations, and thus a clinically important difference be- tween men, women on Triphasil ® , and women not receiving oral contraceptives is unlikely. High inter- and intrasubject variability in DM:3MM and DM:DX were clearly demon - strated and limit the use of dextromethorphan to phenotype endogenous CYP3A4 and CYP2D6 activity. Journal of Clinical Pharmacology, 2001;41:723-731 ©2001 the American College of Clinical Pharmacology