Enhanced bioavailability of a new thiazolidine derivative FPFS-410, an antidiabetic and lipid-lowering drug, after oral administration of its hydroxypropyl-beta-cyclodextrin complex to bile duct-cannulated rats.
The effect of bile acids on bioavailability of FPFS-410 (2-(N-Cyanoimino)-5-{(E)-4-styrylbenzylidene}-4-oxothiazolidine) after oral administration of the drug and its 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CyD) complex was investigated. The complexation with HP-beta-CyD increased the oral bioavailability of FPFS-410 in normal rats in a HP-beta-CyD concentration-dependent manner, compared with that of drug alone. In bile duct-cannulated rats, bile acid concentrations in pylic serum and biliary were decreased to 18% and 14% of sham-operated rats, respectively. After oral administration of the HP-beta-CyD complex, the plasma levels of FPFS-410 were lower in bile duct-cannulated rats than in sham-operated rats up to 1 h, however, this order reversed from 2 to 12 h. The plasma levels of M1, a dominant metabolite of FPFS-410 in rats, significantly decreased until 2 h after administration of the complex in bile duct-cannulated rats, compared with in sham-operated rats. Bioconversion of FPFS-410 to M1 and CYP3A2 expression in the liver was markedly lowered by bile duct-cannulation. Bile duct-cannulation did not, however, affect the serum levels of estradiol. These results suggest that bile acids have a pivotal role for bioavailability of FPFS-410 after oral administration of the FPFS-410 complex with HP-beta-CyD through CYP3A2 activity in liver of rats.
Hara
Takumi
T
Graduate School of Pharmaceutical Sciences, Kumamoto University, Japan.
Arima
Hidetoshi
H
Hirayama
Fumitoshi
F
Uekama
Kaneto
K
D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000284:Administration, Oral; D000818:Animals; D001652:Bile Ducts / Q000187:drug effects / Q000378:metabolism*; D001682:Biological Availability; D002404:Catheterization; D004357:Drug Synergism; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000493:pharmacokinetics*; D000960:Hypolipidemic Agents / Q000737:chemistry / Q000493:pharmacokinetics*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D013844:Thiazoles / Q000737:chemistry / Q000493:pharmacokinetics*; D047392:beta-Cyclodextrins / Q000008:administration & dosage* / Q000493:pharmacokinetics*
C497430:FPFS-410; D007004:Hypoglycemic Agents; D000960:Hypolipidemic Agents; D013844:Thiazoles; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin