Dog S9 Research Articles

Sulfation of selected mono-hydroxyflavones by sulfotransferases in vitro: a species and gender comparison

Sulfation via sulfotransferases is an important metabolic pathway contributing to the low bioavailability of flavonoids. This study aims to characterize the sulfation of mono-hydroxyflavones (MHFs) to obtain useful information on structure-metabolizing relationships in animal species and gender differences. Three representative MHFs, namely, 7-, 6- and 4'-MHF, were studied by incubating each MHF at different concentrations with various liver S9 fractions (mouse, rat, dog and human). One mono-sulfate was identified for each MHF. 7-MHF and 4'-MHF usually have greater sulfations than 6-MHF. Regardless of whether the S9 fraction came from a male or female, there was a difference in sulfation in the species observed for all MHFs; the highest activity of sulfotransferases was in dog S9. Furthermore, gender differences affect sulfation of MHFs significantly. In rats, all sulfations for the three MHFs were higher in males than that in females while the opposite was observed in mice. Regiospecific, species and gender dependence exist in the sulfonation of all selected MHFs.

Nonclinical pharmacokinetics of BMS‐292655, a water‐soluble prodrug of the antifungal ravuconazole

The phosphate ester, BMS-292655, was developed as a water-soluble prodrug of the antifungal agent, ravuconazole (BMS-207147). BMS-292655 was comparatively stable in rat, beagle dog, cynomolgus monkey and human plasma, but was hydrolysed upon incubation with liver S9 preparations from all species. The major product in rat, monkey and human S9 was BMS-207147, while in dog S9, the intermediate ester, BMS-300043, predominated. BMS-300043 itself was more stable in dog S9 than in S9 preparations from the other species. Intravenous administration of BMS-292655 to rats, beagle dogs and cynomolgus monkeys indicated species differences in the extent of formation of BMS-207147 (monkeys>rats>dogs). The lower overall generation of BMS-207147 in dogs was consistent with the presence of circulating plasma levels of BMS-300043. BMS-300043 was present in monkey plasma but not detectable in rat plasma. The conversion of BMS-292655 to BMS-207147 in the presence of human S9 indicated the potential for BMS-292655 to function as a BMS-207147 prodrug in humans. The similarity in the hydrolysis of BMS-292655 when incubated with human and monkey S9 in vitro, coupled with the effective release of BMS-207147 from BMS-292655 upon i.v. administration to monkeys, is consistent with this conclusion.