Pharmacokinetics of midazolam in CYP3A4- and CYP3A5-genotyped subjects.
OBJECTIVE
We investigated whether differences in pharmacokinetics of midazolam, a CYP3A probe, could be demonstrated between subjects with different CYP3A4 and CYP3A5 genotypes.


METHODS
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 micro g of midazolam in 21 healthy subjects.


RESULTS
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 AUC(inf) values between the different genotypes after the 75- micro g or the 7.5-mg dose.


CONCLUSIONS
Presently, CYP3A4 and CYP3A5 genotyping methods do not sufficiently reflect the inter-individual variability of CYP3A activity.
Eap
Chin B
CB
Unit of Biochemistry and Clinical Psychopharmacology, Centre of Psychiatric Neurosciences, University Department of Adult Psychiatry, Hôpital de Cery, 1008 Prilly-Lausanne, Switzerland. Chin.Eap@inst.hospvd.ch
Buclin
Thierry
T
Hustert
Elisabeth
E
Bleiber
Gabriela
G
Golay
Kerry Powell
KP
Aubert
Anne-Catherine
AC
Baumann
Pierre
P
Telenti
Amalio
A
Kerb
Reinhold
R
D019540:Area Under Curve; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008874:Midazolam / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics*
C042940:4-hydroxymidazolam; D003577:Cytochrome P-450 Enzyme System; C040081:1-hydroxymethylmidazolam; C104464:CYP3A protein, human; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D008874:Midazolam