title: Oral administration of a low dose of midazolam (75 microg) as an in vivo probe for CYP3A activity.
abstract: 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.
authors.affiliation: Unit of Biochemistry and Clinical Psychopharmacology, Centre of Psychiatric Neurosciences, University Department of Adult Psychiatry, Prilly-Lausanne, Switzerland. Chin.Eap@inst.hospvd.ch
authors.forename: Chin B
authors.initials: CB
authors.lastname: Eap
authors.forename: Thierry
authors.initials: T
authors.lastname: Buclin
authors.forename: Gianni
authors.initials: G
authors.lastname: Cucchia
authors.forename: Daniele
authors.initials: D
authors.lastname: Zullino
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Hustert
authors.forename: Gabriela
authors.initials: G
authors.lastname: Bleiber
authors.forename: Kerry Powell
authors.initials: KP
authors.lastname: Golay
authors.forename: Anne-Catherine
authors.initials: AC
authors.lastname: Aubert
authors.forename: Pierre
authors.initials: P
authors.lastname: Baumann
authors.forename: Amalio
authors.initials: A
authors.lastname: Telenti
authors.forename: Reinhold
authors.initials: R
authors.lastname: Kerb
mesh_terms: 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*
chemical_list: C042940:4-hydroxymidazolam; C040081:1-hydroxymethylmidazolam; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D008874:Midazolam; D007654:Ketoconazole