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

Abstract

1. 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.

2. 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.

3. 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.

Keywords::

• Midazolam
• triazolam
• alprezolam
• double-cannulation
• rat
• mouse
• portal and systemic blood
• availability

Acknowlegments

Declaration of interest: This work was financially supported in part by Grant-in-Aid for the Scientific Research (17390035) from the Ministry of Education, Sports, Science and Technology of Japan.