Oral administration of a low dose of midazolam (75 microg) as an in vivo probe for CYP3A activity

Eur J Clin Pharmacol. 2004 Jun;60(4):237-46. doi: 10.1007/s00228-004-0762-z. Epub 2004 Apr 28.


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.

Conclusion: 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.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aryl Hydrocarbon Hydroxylases / antagonists & inhibitors
  • Aryl Hydrocarbon Hydroxylases / biosynthesis
  • Aryl Hydrocarbon Hydroxylases / metabolism*
  • Cross-Over Studies
  • Cytochrome P-450 CYP3A
  • Dose-Response Relationship, Drug
  • Enzyme Induction
  • Female
  • Humans
  • Ketoconazole / pharmacology
  • Male
  • Midazolam / administration & dosage*
  • Midazolam / adverse effects
  • Midazolam / analogs & derivatives*
  • Midazolam / blood
  • Midazolam / pharmacokinetics*
  • Middle Aged
  • Oxidoreductases, N-Demethylating / antagonists & inhibitors
  • Oxidoreductases, N-Demethylating / biosynthesis
  • Oxidoreductases, N-Demethylating / metabolism*


  • 4-hydroxymidazolam
  • 1-hydroxymethylmidazolam
  • Aryl Hydrocarbon Hydroxylases
  • Cytochrome P-450 CYP3A
  • Oxidoreductases, N-Demethylating
  • Midazolam
  • Ketoconazole