Influence of gender and oral contraceptives on CYP2D6 and CYP2C19 activity in healthy volunteers.
OBJECTIVE
The study was carried out in order to assess the effects of gender and the use of oral contraceptives (OCs) on CYP2D6 and CYP2C19 activities in healthy volunteers.


METHODS
Six hundred and eleven Caucasian volunteers (330 males and 281 females; age range 18-49 years) were phenotyped with respect to CYP2D6 and CYP2C19 by means of the probe drugs dextromethorphan and mephenytoin, respectively. Extensive metabolisers were selected for this study.


RESULTS
The median dextromethorphan/dextrorphan metabolic ratio in non-OC using females was significantly lower than in males (0.067 vs 0.080; P = 0.033) (mean difference in ln dextromethorphan/dextrorphan metabolic ratio 0.023, 95% CI 0.03-0.43). For the mephenytoin S/R ratio, no such difference was observed. However, OC using females had a significantly higher median mephenytoin S/R ratio than non-OC using females (0.230 vs 0.090; P < 0.001) (mean difference in ln mephenytoin S/R ratio 0.082, 95% CI 0.60-1.04). Moreover, females using combined OCs had a significantly higher median ratio than females using OCs with progestins only (median 0.258 vs 0.135; P = 0.008) (mean difference in ln mephenytoin S/R ratio 0.82, 95% CI 0.21-1.34).


CONCLUSIONS
Given certain assumptions, the study indicates that females in the fertile age have a slightly higher CYP2D6 activity compared with males. There was no evidence of a gender difference in CYP2C19 activity. The use of combined OCs reduces the activity of CYP2C19, an effect that seems to be related to the ethinyloestradiol component.
Hägg
S
S
Division of Clinical Pharmacology, Norrland University Hospital, Umeå, Sweden.
Spigset
O
O
Dahlqvist
R
R
D000293:Adolescent; D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases; D003276:Contraceptives, Oral / Q000494:pharmacology*; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6 / Q000187:drug effects / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000378:metabolism*; D003915:Dextromethorphan / Q000378:metabolism; D003917:Dextrorphan / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000187:drug effects / Q000378:metabolism*; D012737:Sex Factors; D013379:Substrate Specificity
D003276:Contraceptives, Oral; D003917:Dextrorphan; D003915:Dextromethorphan; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6