1.
BOF-4272 (a pyrazolotriazine
sulfoxide) is a new
drug for the treatment of
hyperuricemia. The pharmacokinetics and biotransformation of both
BOF-4272 enantiomers were investigated in rat. 2. Plasma concentrations after intravenous or
oral administration of racemic
BOF-4272 to rat were significantly higher for (S)- than for (R)-BOF-4272. 3. The concentration of (S)-BOF-4272 in hepatocyte culture medium 24 h after the addition of racemic
BOF-4272 was higher than that of (R)-BOF-4272. 4. Liver concentrations after oral adminstration of racemic
BOF-4272 to rat were significantly higher for (R)- than for (S)-BOF-4272. Kidney concentrations were significantly higher for (S)- than for (R)-BOF-4272. 5. Hepatic biotransformation from
BOF-4272 to unknown metabolites, possibly conjugates, is stereoselective. Biotransformation of both enantiomers to the
sulfone metabolite by
cytochrome P450 in rat liver may also be stereoselective. 6. Biotransformation of the
sulfide metabolite of
BOF-4272 to
BOF-4272 may be stereoselective, possibly due to the stereospecificity of
flavin-containing mono-
oxidase and/or cyrochrome P450. 7. The stereoselectivity of plasma concentrations of racemic
BOF-4272 after intravenous or
oral administration appears to be due to differences in the hepatic uptake of the two enantiomers as well as the stereoselective biotransformation of the
sulfide metabolite to
BOF-4272 in rat liver. Biotransformation of
BOF-4272 in rat liver may also be stereoselective.