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 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 (AUC(por)) to that in systemic blood (AUC(sys)) 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.
Kuze
J
J
Evaluation Research Laboratory, Hanno Research Center, Taiho Pharmaceutical Co., Ltd, Saitama, Japan.
Mutoh
T
T
Takenaka
T
T
Morisaki
K
K
Nakura
H
H
Hanioka
N
N
Narimatsu
S
S
D000284:Administration, Oral; D000525:Alprazolam / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D000818:Animals; D001569:Benzodiazepines / Q000737:chemistry / Q000493:pharmacokinetics*; D001682:Biological Availability; D002404:Catheterization; D007413:Intestinal Mucosa / Q000378:metabolism*; D007601:Jugular Veins; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008874:Midazolam / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D011169:Portal Vein; D051381:Rats; D017207:Rats, Sprague-Dawley; D014229:Triazolam / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*
D001569:Benzodiazepines; D014229:Triazolam; D008874:Midazolam; D000525:Alprazolam