In vitro and in vivo studies on the stereoselective pharmacokinetics and biotransformation of an (S)-(–)- and (R)-(+)-pyrazolotriazine sulfoxide in the male rat

Abstract

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.