Js. Mccune et al., Lack of gender differences and large intrasubject variability in cytochrome P450 activity measured by phenotyping with dextromethorphan, J CLIN PHAR, 41(7), 2001, pp. 723-731
Gender-based differences in cytochrome P450 (CYP) activity may occur due to
endogenous hormonal fluctuations with the menstrual cycle, which ore alter
ed by oral contraceptives. This study assessed the average activity and wit
hin-subject variability in CYP3A4 and CYP2D6 in men, women taking Triphasil
(R), and regularly menstruating women not receiving oral contraceptives. T
hirty-three healthy volunteers participated in this 28-day pilot study (12
women receiving Triphasil (R)) (OCs) 12 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:dext
rorphan (DX) respectively. Serial blood concentrations of estrogen and prog
esterone and menstrual diaries were used to determine menstrual phase in bo
th groups of women. Average urinary DM:3MM and DM:DX in the 28 extensive me
tabolizers of CYP2D6 did nor 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 dextr
omethorphan and its metabolites 3MM and DX. Variability in CYP3A4 and CYP2D
6 activity, characterized by intrasubject standard deviation, also did not
differ. The varying doses of levonorgesterol and ethinyl estradiol in Triph
asil (R), fluctuations in estrogen and progesterone, and menstrual phase di
d not influence CYP3A4 or CYP2D6 activity. It was concluded that CYP3A4 and
CYP2D6 activity and intrasubject variability were not different in the thr
ee study populations, and thus a clinically important difference between me
n, women on Triphasil (R), and women not receiving oral contraceptives is u
nlikely. High inter- and intrasubject variability in DM:3MM and DM:DX were
clearly demonstrated and limit the use of dextromethorphan to phenotype end
ogenous CYP3A4 and CYP2D6 activity.