摘要：8-(3-methoxy-4-phenylsulfinylphenyl) pyrazolo[1, 5-a]-1, 3, 5-triazine-4(1H)-one (BOF-4272) blocks xanthine oxidase/xanthine dehydrogenase in the liver. BOF-4272 with a sulfoxide chiral center includes R(+)- and S(-)- enantiomers. The enantioselectivity in the global disposition of BOF-4272 can be attributed to that in the local disposition of organs, especially the liver. Thus, the enantioselectivity in the hepatic local disposition of BOF-4272 was compared between R- and S-enantiomers by a hepatic perfusion experiment with a pulse input into the portal vein. The influence of perfusate albumin on the enantioselective local disposition was also investigated. The elution time profile of each BOF-4272 enantiomer from the liver into the hepatic vein was measured at four different bovine serum albumin (BSA) concentrations (0, 0.25, 1.0 and 4.0%) in the perfusate at 37 and 4°C. A crossover test was carried out for R- and S-enantiomers using one rat liver. In the absence of perfusate BSA at 37°C, hepatic extraction ratios (EH) of R- and S-enantiomers of BOF-4272 were 75.6±4.3% and 71.7±3.3%, respectively, which were statistically the same. In the presence of 4.0% BSA at 37°C, EH values of R- and S-enantiomers were 31.7±4.6% and 19.6±3.8%, respectively, which demonstrated that EH of R-enantiomer was significantly greater than that of S-enantiomer (p<0.001). In the absence and presence of perfusate BSA at 4°C, there was no significant difference in EH between S- and R-enantiomers. An amplification of stereoselectivity with albumin was observed by the perfusion experiment using BOF-4272 enantiomers.
关键词：BOF-4272;stereoselective local disposition;perfusate albumin;xanthine oxidase inhibitor
