Pharmacokinetics of midazolam in CYP3A4- and CYP3A5-genotyped subjects
We investigated whether differences in pharmacokinetics of midazolam, a CYP3A probe, could be demonstrated between subjects with different CYP3A4 and CYP3A5 genotypes.
Plasma concentrations of midazolam, and of total (conjugated + unconjugated) 1′OH-midazolam, and 4′OH-midazolam were measured after the oral administration of 7.5 mg or of 75 µg of midazolam in 21 healthy subjects.
CYP3A5*7, CYP3A4*1E, CYP3A4*2, CYP3A4*4, CYP3A4*5, CYP3A4*6, CYP3A4*8, CYP3A4*11, CYP3A4*12, CYP3A4*13, CYP3A4*17 and CYP3A4*18 alleles were not identified in the 21 subjects. CYP3A5*3, CYP3A5*6, CYP3A4*1B and CYP3A4*1F alleles were identified in 20, 1, 4 and 2 subjects, respectively. No statistically significant differences were observed for the AUCinf values between the different genotypes after the 75-µg or the 7.5-mg dose.
Presently, CYP3A4 and CYP3A5 genotyping methods do not sufficiently reflect the inter-individual variability of CYP3A activity.
KeywordsCYP3A4 CYP3A5 Phenotyping
The authors thank Mrs V. Sari and Mrs C. Bertschi for editorial assistance, Mrs E. Ponce, Mrs J. Rosselet and Mrs M. Gobin for bibliographic help. This work was supported in part by the Swiss National Research Foundation (project 3200–065427.01).
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