Effect of temperature in perfusate on local hepatic disposition of BOF-4272, a new xanthine oxidase inhibitor.

Abstract

The effect of temperature on the local hepatic disposition of BOF-4272 [(+/-)-8-(3-methoxy-4-phenylsulfinyl-phenyl)pyrazolo[1,5-a]-1,3,5- triazine-4-olate], a new drug used to treat hyperuricemia, was investigated by means of a perfusion experiment following the pulse input into the portal vein of rat, in which the temperature of the perfusate was changed from 37 degrees C down to 4 degrees C. The same perfusion experiment was also attempted using bovine serum albumin (BSA) as a reference substance to compare with the hepatic disposition of BOF-4272. The elution time profiles of BOF-4272 and BSA from the liver into the hepatic vein were evaluated by moment analysis. The recovery ratio (FH) and the mean transit time (tH) of BOF-4272 were 22.8 +/- 3.3% and 0.111 +/- 0.008 min at 37 degrees C, respectively. Both FH and tH significantly increased with the decrease in the temperature of the perfusate, 3 times and 2 times greater at 4 degrees C than at 37 degrees C, respectively. The FH and tH of BSA were 98.3 +/- 4.5% and 0.129 +/- 0.013 min at 37 degrees C, respectively. These parameters of BSA were independent of temperature, while those of BOF-4272 showed a definite dependency on temperature. A new estimation method for the elimination rate constant (kc) and the partition ratio (k') in the dispersion model was developed by rearranging the theoretical equations of FH and tH. The index for the elimination (ke) of BOF-4272 decreased with the decrease in temperature, while the index for the distribution (k') increased with the decrease in temperature. This result shows that the metabolism (or the biliary excretion) decreased and the distribution increased with a decrease in temperature, indicating that the hepatic metabolizing pathway which is presumably temperature-dependent is blocked, and the blocked portion of BOF-4272 thus returns back to the perfusate at the low temperature.