Effect of the CYP3A5 genotype on the pharmacokinetics of intravenous midazolam during inhibited and induced metabolic states

Clin Pharmacol Ther. 2004 Aug;76(2):104-12. doi: 10.1016/j.clpt.2004.03.009.


Objective: Our objective was to investigate the effect of the CYP3A5 genotype on the systemic clearance of midazolam in constitutive, inhibited, and induced metabolic conditions.

Methods: Nineteen healthy volunteers were grouped with regard to the CYP3A5*3 allele, into homozygous wild-type (CYP3A5*1/*1, n = 6), heterozygous (CYP3A5*1/*3, n = 6), and homozygous variant-type (CYP3A5*3/*3, n = 7) subject groups. The pharmacokinetic profile of intravenous midazolam was characterized before and after itraconazole administration (200 mg once daily for 4 days) and also after rifampin (INN, rifampicin) pretreatment (600 mg once daily for 10 days), with a washout period of 2 weeks in between.

Results: The pharmacokinetic profiles of midazolam and of its hydroxy metabolites did not show differences between the genotype groups under basal and induced metabolic conditions. However, during the inhibited metabolic state, the CYP3A5*3/*3 group showed a greater decrease in systemic clearance than was seen in the CYP3A5*1/*1 group (8.5 +/- 3.8 L. h(-1). 70 kg(-1) versus 13.5 +/- 2.7 L. h(-1). 70 kg(-1), P =.027). The 1'-hydroxymidazolam-to-midazolam area under the plasma concentration-time curve ratio was also significantly lower in the CYP3A5*3/*3 group (0.58 +/- 0.35 versus 1.09 +/- 0.37 for the homozygous wild-type group, P =.026).

Conclusions: The CYP3A5 genotype did not affect the pharmacokinetics of intravenous midazolam in the basal or induced states. However, during cytochrome P450 (CYP) 3A inhibition by itraconazole, individuals carrying the CYP3A5*1 allele were found to be less susceptible to changes in systemic clearance and showed higher 1'-hydroxymidazolam-to-midazolam area under the plasma concentration-time curve ratios, probably resulting from the relatively CYP3A4-specific inhibition caused by itraconazole.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Asian Continental Ancestry Group / genetics*
  • Biological Availability
  • Biotransformation
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme System / drug effects*
  • Cytochrome P-450 Enzyme System / genetics*
  • Female
  • Genetic Variation
  • Genotype
  • Humans
  • Infusions, Intravenous
  • Itraconazole / pharmacology
  • Male
  • Metabolic Clearance Rate
  • Midazolam / administration & dosage
  • Midazolam / pharmacokinetics*
  • Pharmacogenetics
  • Polymorphism, Genetic*
  • Prospective Studies
  • Rifampin / pharmacology
  • Sensitivity and Specificity


  • Itraconazole
  • Cytochrome P-450 Enzyme System
  • CYP3A protein, human
  • CYP3A5 protein, human
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • Midazolam
  • Rifampin