Quantification of 3-month intraindividual variability and the influence of sex and menstrual cycle phase on CYP3A activity as measured by phenotyping with intravenous midazolam.
OBJECTIVE
Intraindividual variability and the effects of sex and menstrual cycle phase on CYP3A activity were evaluated by phenotyping with use of midazolam as the probe drug.


METHODS
Midazolam (0.025 mg/kg) was administered intravenously to 10 white male volunteers every 14 days for 3 months and to 10 white premenopausal female volunteers during the midfollicular and midluteal phases of the menstrual cycle for 3 complete cycles. Serum was collected for a 6-hour period, and enzyme activity was represented by midazolam plasma clearance.


RESULTS
No difference in clearance was observed during the menstrual cycle phases. Mean +/- SD midazolam clearance was 0.00816 +/- 0.00252 L/min/kg during the midfollicular phase and 0.00818 +/- 0.00224 during the midluteal phase (P = .96). When the menstrual cycle phases were combined, mean midazolam clearance in women was 0.00817 +/- 0.00235 L/min/kg. Mean male midazolam clearance was 0.00766 +/ 0.00167 L/min/kg. There was no difference in midazolam clearance between men and women (P = .68). Coefficients of variation (CV%) for the 6 phenotyping visits were calculated and the median midazolam clearance CV% (25th to 75th percentile) was 9.75% (8.40% to 11.5%).


CONCLUSIONS
Because no significant differences in midazolam clearance were noted between menstrual cycle phases or between sexes, pharmacokinetic and clinical investigations of CYP3A activity in adults may not require stratification on the basis of menstrual cycle phase or sex.
Kashuba
A D
AD
Department of Medicine, Bassett Healthcare, Cooperstown, NY 13326-1394, USA.
Bertino
J S
JS
Rocci
M L
ML
Kulawy
R W
RW
Beck
D J
DJ
Nafziger
A N
AN
D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005260:Female; D005498:Follicular Phase / Q000502:physiology; D006801:Humans; D006900:Hydroxylation; D006993:Hypnotics and Sedatives / Q000097:blood*; D007262:Infusions, Intravenous; D008183:Luteal Phase / Q000502:physiology; D008297:Male; D008597:Menstrual Cycle / Q000502:physiology*; D008874:Midazolam / Q000097:blood*; D008875:Middle Aged; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism*; D010641:Phenotype; D012016:Reference Values; D012727:Sex Characteristics; D013997:Time Factors
D006993:Hypnotics and Sedatives; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D008874:Midazolam