Dose-dependent intestinal and hepatic first-pass metabolism of midazolam, a cytochrome P450 3A substrate with differently modulated enzyme activity in rats

J Pharm Pharmacol. 1999 Jan;51(1):67-72. doi: 10.1211/0022357991771971.


The dose-dependent first-pass metabolism of midazolam, a cytochrome P450 (CYP) 3A substrate, was separately estimated in the intestine and liver after administration into a jejunal loop of rats with differently modulated enzyme activity. Modulation of CYP3A enzyme activity of Sprague-Dawley rats was performed by pretreating the rats with inducers such as dexamethasone or by co-administering ketoconazole (an inhibitor) with midazolam. Bioavailabilities of midazolam administered into the jejunal loop at a dose of 10 micromol were 12% in untreated (control) rats, and 2% in dexamethasone-pretreated rats. Co-administered ketoconazole (2 micromol) significantly increased the bioavailability to 53% and 7%, respectively, in these rats. The intestinal first-pass metabolism of midazolam administered into the jejunal loop at a dose of 50 nmol in untreated and dexamethasone-pretreated rats, estimated by the mesenteric blood-collecting method in-situ, was 25% and 49% of absorbed amount, respectively. The intestinal first-pass metabolism of midazolam was reduced when ketoconazole (0.5 micromol) was co-administered or when the dose of midazolam was increased to 0.5 micrommol in these rats. Assuming that the contribution of intestinal first-pass metabolism could be negligible when midazolam was administered at a much higher dose of 10 micromol, the estimated hepatic first-pass metabolism of midazolam at a dose of 10 micromol in untreated rats, dexamethasone-pretreated rats, untreated rats given ketoconazole, and dexamethasone-pretreated rats given ketoconazole was, respectively, 86, 97, 46, and 92% of the amounts absorbed. In conclusion, the dose-dependent intestinal first-pass metabolism and the hepatic first-pass metabolism of midazolam in rats with differently modulated CYP3A activities was quantitatively estimated by in-vivo and in-situ absorption studies.

MeSH terms

  • Animals
  • Antifungal Agents / pharmacology
  • Aryl Hydrocarbon Hydroxylases*
  • Biological Availability
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme System / drug effects
  • Cytochrome P-450 Enzyme System / metabolism
  • Cytochrome P-450 Enzyme System / physiology*
  • Dexamethasone / pharmacology*
  • Dose-Response Relationship, Drug
  • Injections, Intravenous
  • Intestinal Mucosa / metabolism*
  • Ketoconazole / pharmacology*
  • Liver / metabolism*
  • Male
  • Midazolam / administration & dosage
  • Midazolam / blood
  • Midazolam / metabolism*
  • Oxidoreductases, N-Demethylating / drug effects
  • Oxidoreductases, N-Demethylating / metabolism
  • Oxidoreductases, N-Demethylating / physiology*
  • Rats
  • Rats, Sprague-Dawley


  • Antifungal Agents
  • Dexamethasone
  • Cytochrome P-450 Enzyme System
  • Aryl Hydrocarbon Hydroxylases
  • Cytochrome P-450 CYP3A
  • Oxidoreductases, N-Demethylating
  • Midazolam
  • Ketoconazole