Local disposition of a new xanthine oxidase/xanthine dehydrogenase inhibitor, BOF-4272, in rat liver.

Abstract

The local hepatic disposition of BOF-4272, a newly developed xanthine oxidase (XO)/xanthine dehydrogenase (XDH) inhibitor, was evaluated in the rat perfusion system following pulse input of the drug into the portal vein. The elution time profiles from the liver into the hepatic vein were analyzed by dispersion models. The disposition of BOF-4272 through the rat liver was represented by a two-compartment dispersion model based on the Akaike's Information Criterion (AIC). The area under the concentration time curve (aucH) of BOF-4272 was proportional to the dosing amount, and the mean transit time was constant from 62.5 up to 500 micrograms/liver, which demonstrates that the local hepatic disposition of BOF-4272 is linear in this dosing range. The local disposition parameters were precisely estimated at the dosing amount of 250 micrograms/liver using several rats. These parameters in the dispersion model were correlated to the local moment characteristics. The hepatic recovery ratio (FH) was 22.8 +/- 3.2% and the mean transit time (tH) was 0.112 +/- 0.008 min, which show that the influx of BOF-4272 into the liver is efficiently large.