Abstract
1. The drug metabolism and pharmacokinetics of S-777469 were investigated in in vitro (rat, dog and human) and in in vivo (rats and dogs).
2. S-777469 was rapidly and well absorbed, with bioavailability values ranging from 50 to 70% in rats and dogs, almost all drug radioactivity was excreted into the feces via bile within 48 h. Thus, good pharmacokinetics of S-777469 (e.g. systemic exposure and excretion rate) would be anticipated in humans.
3. In vitro metabolism of S-777469 was qualitatively similar in rat, dog and human hepatocytes. S-777469 acyl glucuronide, S-777469 5-hydroxymethyl and S-777469 4-hydroxycyclohexane were the main metabolites in rats, dogs and humans. In vivo metabolism in rats and dogs showed good qualitative agreement with in vitro metabolism, and no metabolites exceeded 10% of total radioactivity in rat and dog plasma.
4. No unique metabolites were observed in human hepatocytes. Therefore, rats and dogs were thought to be appropriate species for non-clinical toxicity studies.
5. In conclusion, these data should be useful for the characterization of the pharmacokinetic properties of S-777469 and the estimation of its pharmacokinetic fate in humans.
Acknowledgements
The authors would like to thank all the members of Shionogi Co., Ltd who assisted with the preclinical studies of S-777469.