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

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...

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Bibliographic Details
Published in:Xenobiotica 2009-11, Vol.39 (11), p.871-880
Main Authors: Kuze, J., Mutoh, T., Takenaka, T., Morisaki, K., Nakura, H., Hanioka, N., Narimatsu, S.
Format: Article
Language:English
Subjects:
Administration, Oral
Alprazolam - administration & dosage
Alprazolam - chemistry
Alprazolam - pharmacokinetics
alprezolam
Animals
availability
Benzodiazepines - chemistry
Benzodiazepines - pharmacokinetics
Biological Availability
Catheterization
double-cannulation
Intestines - metabolism
Jugular Veins
Liver - metabolism
Male
Mice
Mice, Inbred BALB C
Midazolam
Midazolam - administration & dosage
Midazolam - chemistry
Midazolam - pharmacokinetics
mouse
portal and systemic blood
Portal Vein
rat
Rats
Rats, Sprague-Dawley
triazolam
Triazolam - administration & dosage
Triazolam - chemistry
Triazolam - pharmacokinetics
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Summary: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 (Fh) 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 (AUCpor) to that in systemic blood (AUCsys) and Fh 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.
ISSN:0049-8254
1366-5928
DOI:10.3109/00498250903215382