The metabolism and pharmacokinetics of [¹⁴C]-S-777469, a new cannabinoid receptor 2 selective agonist, in healthy human subjects

Abstract

1. The metabolism and pharmacokinetics of S-777469 were investigated after a single oral administration of [¹⁴C]-S-777469 to healthy human subjects.

2. Total radioactivity was rapidly and well absorbed in humans, with C_max of 11 308 ng eq. of S-777469/ml at 4.0 h. The AUC_inf ratio of unchanged S-777469 to total radioactivity was approximately 30%, indicating that S-777469 was extensively metabolized in humans.

3. The metabolite profiling in human plasma showed that S-777469 5-carboxymethyl (5-CA) and S-777469 5-hydroxymethyl (5-HM) were the main circulating metabolites, and the AUC_inf ratio of 5-CA and 5-HM to total radioactivity were 24 and 9.1%, respectively. These data suggest that S-777469 was subsequently metabolized to 5-CA in humans although the production amount of 5-CA was extremely low in human hepatocytes.

4. Total radioactivity was mainly excreted via the feces, with 5-CA and 5-HM being the main excretory metabolites in feces and urine. Urinary excretion of 5-CA was comparable with that of 5-HM, whereas fecal excretion of 5-CA was lower than that of 5-HM.

5. In conclusion, the current mass balance study revealed the metabolic and pharmacokinetic properties of S-777469 in humans. These data should be useful to judge whether or not the safety testing of metabolite of S-777469 is necessary.

• Cannabinoid receptor 2 selective agonist
• human mass balance study
• metabolite profiling
• pharmacokinetics
• radiolabeled S-777469

Acknowledgements

The authors would like to thank all the members of Shionogi Co., Ltd. who assisted with the mass balance studies of S-777469 in the clinical research.

Declaration of interest

The authors declare no conflicts of interest.

Supplementary material available online

Supplemental Tables S1 and S2