Oral administration of a low dose of midazolam (75 microg) as an in vivo probe for CYP3A activity.
OBJECTIVE
We investigated whether the oral administration of a low dose (75 micro g) of midazolam, a CYP3A probe, can be used to measure the in vivo CYP3A activity.


METHODS
Plasma concentrations of midazolam, 1'OH-midazolam and 4'OH-midazolam were measured after the oral administration of 7.5 mg and 75 micro g midazolam in 13 healthy subjects without medication, in four subjects pretreated for 2 days with ketoconazole (200 mg b.i.d.), a CYP3A inhibitor, and in four subjects pretreated for 4 days with rifampicin (450 mg q.d.), a CYP3A inducer.


RESULTS
After oral administration of 75 micro g midazolam, the 30-min total (unconjugated + conjugated) 1'OH-midazolam/midazolam ratios measured in the groups without co-medication, with ketoconazole and with rifampicin were (mean+/-SD): 6.23+/-2.61, 0.79+/-0.39 and 56.1+/-12.4, respectively. No side effects were reported by the subjects taking this low dose of midazolam. Good correlations were observed between the 30-min total 1'OH-midazolam/midazolam ratio and midazolam clearance in the group without co-medication (r(2)=0.64, P<0.001) and in the three groups taken together (r(2)=0.91, P<0.0001). Good correlations were also observed between midazolam plasma levels and midazolam clearance, measured between 1.5 h and 4 h.


CONCLUSIONS
A low oral dose of midazolam can be used to phenotype CYP3A, either by the determination of total 1'OH-midazolam/midazolam ratios at 30 min or by the determination of midazolam plasma levels between 1.5 h and 4 h after its administration.
Eap
Chin B
CB
Unit of Biochemistry and Clinical Psychopharmacology, Centre of Psychiatric Neurosciences, University Department of Adult Psychiatry, Prilly-Lausanne, Switzerland. Chin.Eap@inst.hospvd.ch
Buclin
Thierry
T
Cucchia
Gianni
G
Zullino
Daniele
D
Hustert
Elisabeth
E
Bleiber
Gabriela
G
Golay
Kerry Powell
KP
Aubert
Anne-Catherine
AC
Baumann
Pierre
P
Telenti
Amalio
A
Kerb
Reinhold
R
D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction; D005260:Female; D006801:Humans; D007654:Ketoconazole / Q000494:pharmacology; D008297:Male; D008874:Midazolam / Q000008:administration & dosage* / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics*; D008875:Middle Aged; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*
C042940:4-hydroxymidazolam; C040081:1-hydroxymethylmidazolam; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D008874:Midazolam; D007654:Ketoconazole