Dose-dependent intestinal and hepatic first-pass metabolism of midazolam, a cytochrome P450 3A substrate with differently modulated enzyme activity in rats.
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.
Higashikawa
F
F
Institute of Pharmaceutical Sciences, Hiroshima University School of Medicine, Japan.
Murakami
T
T
Kaneda
T
T
Kato
A
A
Takano
M
M
D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology; D001189:Aryl Hydrocarbon Hydroxylases; D001682:Biological Availability; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D003907:Dexamethasone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D007275:Injections, Intravenous; D007413:Intestinal Mucosa / Q000378:metabolism*; D007654:Ketoconazole / Q000494:pharmacology*; D008099:Liver / Q000378:metabolism*; D008297:Male; D008874:Midazolam / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism*; D010089:Oxidoreductases, N-Demethylating / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000935:Antifungal Agents; D003907:Dexamethasone; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D008874:Midazolam; D007654:Ketoconazole