CYP2D6 and CYP2C19 activity in a large population of Dutch healthy volunteers: indications for oral contraceptive-related gender differences.
OBJECTIVE
We examined a large database containing results on CYP2D6 and CYP2C19 activity of 4301 Dutch volunteers phenotyped in the context of various clinical pharmacology studies.


METHODS
The subjects were given 22 mg dextromethorphan, 100 mg mephenytoin and 200 mg caffeine. For CYP2D6, the dextromethorphan/dextrorphan metabolic ratios in urine samples taken for a subsequent 8 h were used. Dextromethorphan and dextrorphan were quantified by reversed-phase high performance liquid chromatography. For CYP2C19 similarly obtained (R)-mephenytoin and (S)-mephenytoin ratios were used. (S)-mephenytoin and (R)-mephenytoin were analysed and quantified by enantioselective capillary gas chromatography. In addition, CYP2C19 poor metabolizer (PM) subjects were reanalysed after acidic pre-treatment of urine samples to confirm the PM status.


RESULTS
The investigated population mainly comprised Caucasian (98.9%) males (68%). The age ranged from 18 to 82 years. For CYP2D6, it was found that 8.0% of the subjects were PMs. The average metabolic ratio was 0.014 (0.033) for subjects who showed extensive metabolizing activity (EM) and 5.4 (7.6) for PM subjects. For CYP2C19, it was found that 1.8% of the subjects were PMs. The metabolic ratio was 0.162 (0.124) for EM subjects and 1.076 (0.040) for PM subjects. Within the EM group the metabolic ratio in females was significantly lower for CYP2D6 (-20%) and significantly higher for CYP2C19 (+40%) compared with males. For PMs there was no such difference for CYP2D6 (P = 0.79) or CYP2C19 (P = 0.20). Oral contraceptive (OC) use significantly decreased the CYP2C19 activity by 68% for mephenytoin as compared to non-OC using females.


CONCLUSIONS
For CYP2D6, the PM incidence (8.0%) is in accordance with literature data. The CYP2C19, PM incidence (1.8%) is low compared to reports from other European countries. For mephenytoin, the acidification procedure has been shown to be very important for the confirmation of CYP2C19 PMs. In EM females compared to EM males, CYP2D6 activity is increased and CYP2C19 activity is reduced. For CYP2C19 in particular this reduction is substantial and most pronounced in the age range from 18 to 40 years. For CYP2C19, the reduced activity is associated with the use of oral contraceptives.
Tamminga
W J
WJ
Pharma Bio-Research International B.V., Zuidlaren, The Netherlands. WTamminga@pbr.nl
Wemer
J
J
Oosterhuis
B
B
Weiling
J
J
Wilffert
B
B
de Leij
L F
LF
de Zeeuw
R A
RA
Jonkman
J H
JH
D000328:Adult; D000368:Aged; D000375:Aging / Q000502:physiology; D001189:Aryl Hydrocarbon Hydroxylases; D003276:Contraceptives, Oral; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics / Q000378:metabolism*; D009426:Netherlands; D010641:Phenotype; D012727:Sex Characteristics; D044465:White People / Q000235:genetics
D003276:Contraceptives, Oral; 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