In-vivo Sex Differences in Disposition and Metabolism of Sulphoxide-containing Drug BOF-4272 in Rats

Abstract

Detailed sex differences in the disposition and metabolism of BOF-4272, a newly developed xanthine oxidase/xanthine dehydrogenase inhibitor, are described on the basis of in-vivo studies in rats. In both male and female rats, at all times after oral administration of 14C-labelled BOF-4272, the highest level of radioactivity (except for radioactivity in the gastrointestinal tract) was observed in the liver, then in the kidney. Little radioactivity was detected in other tissues. After oral administration the total 14C concentration profiles in the plasma and kidney were almost identical in male and female rats whereas total 14C concentrations in the liver to 24h were higher in female rats than in males. Levels of BOF-4269 (the sulphide metabolite of BOF-4272) in the contents of the large intestine to 24h after the oral administration of BOF-4272 were higher in female rats than in males. BOF-4269 was the main metabolite found in the plasma in female rats after intravenous or oral administration. The area under the plasma concentration-time curve (AUC0-t) for BOF-4272 after oral administration was almost identical in female and male rats, whereas that for BOF-4269 was 2.8 times higher in female rats than in males. These findings suggest that differences between the disposition of 14C-labelled BOF-4272 in rats of different sexes are mainly because of differences between the metabolism of BOF-4272 to BOF-4269 by the intestinal flora, the elimination of BOF-4269 by the liver, or both.