Assessment of the hepatic and intestinal first-pass metabolism of midazolam in a CYP3A drug-drug interaction model rats.
In the current study, to understand the characteristics of dexamethasone (DEX)-treated female rats as an animal model for drug-drug interactions, a double-cannulation method was applied and separately assessed for the intestinal and hepatic first-pass metabolism of midazolam. Midazolam was administered intravenously or orally to the animals, and midazolam concentrations in the portal and systemic plasma were simultaneously determined. Next, the rates of elimination from the intestine and liver were estimated using the AUC values. After oral administration of midazolam, the entire drug was absorbed without intestinal first-pass metabolism, and 93% of the administered midazolam was extracted in the liver of the DEX-treated female rats. Seven per cent of the midazolam administered reached the systemic circulation. When ketoconazole was given orally to the animals, in conjunction with midazolam, the extraction ratio in the liver decreased from 93% to 77% in the control rats, and the bioavailability of midazolam increased to 23%. On the other hand, after intravenous administration, the elimination half-life of midazolam was not changed by ketoconazole pretreatment. These results indicated that midazolam is only extracted in the liver of DEX-treated female rats and that ketoconazole inhibits the hepatic first-pass metabolism, but not the systemic metabolism. In conclusion, DEX-treated female rats can be used as a drug-drug interaction model via CYP3A4 enzyme inhibition, especially for the hepatic first-pass metabolism of orally administered drugs.
Kanazu
Takushi
T
Developmental Research Laboratories, Shionogi & Co., Ltd, 1-1, 3-chome, Futaba-cho, Toyonaka-shi, Osaka, Japan 561-0825. takushi.kanazu@shionogi.co.jp
Okamura
Noboru
N
Yamaguchi
Yoshitaka
Y
Baba
Takahiko
T
Koike
Masahiro
M
D000818:Animals; D014151:Anti-Anxiety Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D000935:Antifungal Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D001711:Biotransformation / Q000187:drug effects; D051544:Cytochrome P-450 CYP3A; D003907:Dexamethasone / Q000008:administration & dosage / Q000493:pharmacokinetics; D004347:Drug Interactions; D005260:Female; D007413:Intestinal Mucosa / Q000378:metabolism; D007654:Ketoconazole / Q000008:administration & dosage / Q000493:pharmacokinetics; D008099:Liver / Q000201:enzymology; D008874:Midazolam / Q000008:administration & dosage / Q000493:pharmacokinetics*; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D014151:Anti-Anxiety Agents; D000893:Anti-Inflammatory Agents; D000935:Antifungal Agents; D003907:Dexamethasone; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D008874:Midazolam; D007654:Ketoconazole