title: Lack of gender differences and large intrasubject variability in cytochrome P450 activity measured by phenotyping with dextromethorphan.
abstract: 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 participated 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 concentrations 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 extensive 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 (alpha = 0.05) to detect a +/- 15% difference from the population mean in the urinary ratios of dextromethorphan and its metabolites 3MM and DX. Variability in CYP3A4 and CYP2D6 activity, characterized by intrasubject standard deviation, also did not differ. The varying doses of levonorgesterol and ethinyl estradiol in Triphasil, fluctuations in estrogen and progesterone, and menstrual phase did not influence CYP3A4 or CYP2D6 activity. 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 between 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 demonstrated and limit the use of dextromethorphan to phenotype endogenous CYP3A4 and CYP2D6 activity.
authors.affiliation: University of Washington, Seattle, USA.
authors.forename: J S
authors.initials: JS
authors.lastname: McCune
authors.forename: C
authors.initials: C
authors.lastname: Lindley
authors.forename: J L
authors.initials: JL
authors.lastname: Decker
authors.forename: K M
authors.initials: KM
authors.lastname: Williamson
authors.forename: A M
authors.initials: AM
authors.lastname: Meadowcroft
authors.forename: D
authors.initials: D
authors.lastname: Graff
authors.forename: W T
authors.initials: WT
authors.lastname: Sawyer
authors.forename: D K
authors.initials: DK
authors.lastname: Blough
authors.forename: J A
authors.initials: JA
authors.lastname: Pieper
mesh_terms: D000328:Adult; D000704:Analysis of Variance; D003277:Contraceptives, Oral, Combined / Q000494:pharmacology*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D003915:Dextromethorphan / Q000378:metabolism* / Q000652:urine; D019304:Ethinyl Estradiol-Norgestrel Combination / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000378:metabolism* / Q000652:urine; D005260:Female; D006801:Humans; D008297:Male; D008598:Menstruation / Q000378:metabolism*; D006899:Mixed Function Oxygenases / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D010865:Pilot Projects; D012727:Sex Characteristics
chemical_list: D003277:Contraceptives, Oral, Combined; D018691:Excitatory Amino Acid Antagonists; D003915:Dextromethorphan; D019304:Ethinyl Estradiol-Norgestrel Combination; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human