| Title | Separate evaluation of intestinal and hepatic metabolism of three benzodiazepines in rats with cannulated portal and jugular veins: comparison with the profile in non-cannulated mice. | | Author(s) | Kuze J, Mutoh T, Takenaka T, Morisaki K, Nakura H, Hanioka N, Narimatsu S | | Institution | Evaluation Research Laboratory, Hanno Research Center, Taiho Pharmaceutical Co., Ltd, Saitama, Japan. | | Source | Xenobiotica 2009 Nov; 39(11):871-80. | | Abstract | Pharmacokinetic analyses of three kinds of benzodiazepines-midazolam (MDZ), triazolam (TRZ) and alprezolam (APZ)-were performed in rats with cannulated portal and jugular veins. Each drug was administered to the double-cannulated rats, and pharmacokinetic data for the parent drugs and their 1'- and 4-hydroxylated metabolites were compared with those obtained in non-cannulated mice. In bioavailability, the drugs ranked APZ >> TRZ = MDZ in rats, and APZ > TRZ >> MDZ in mice, with the values for MDZ remarkably different between rats and mice (19% in rats versus 2.3% in mice). In contrast, hepatic availability (F(h)) was similar (APZ > TRZ > MDZ) in both species. Highly significant relationships were found between the ratio of the area under the plasma concentration-time curve (AUC) for the parent drugs in portal blood (AUC(por)) to that in systemic blood (AUC(sys)) and F(h) in rats and mice. The double-cannulated rat is useful for estimating the hepatic availability of drug candidates by determining the AUC values for the parent drugs in portal and systemic blood samples. | | Language | eng | | Pub Type(s) | Journal Article
| | PubMed ID | 19845438 |
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