Non-clinical evaluation of the metabolism, pharmacokinetics and excretion of S-777469, a new cannabinoid receptor 2 selective agonist

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.

Cannabinoids in Medicine: A Multifaceted Exploration of Types, Therapeutic Applications, and Emerging Opportunities in Neurodegenerative Diseases and Cancer Therapy

“…These studies not only predict human pharmacokinetic properties but also help establish correlations with pharmacodynamic assessments in commonly employed animal models for nonclinical investigations. The employment of specialized methodologies, such as [14C]-S-777469, has proven to be invaluable for the in-depth analysis of specific agonists like S-777469, offering nuanced insights into their behavior within human systems and broadening the understanding of their pharmacological profiles [ 87 ].…”

Medicinal Chemistry, Pharmacology, and Potential Therapeutic Benefits of Cannabinoid CB2 Receptor Agonists

“…AZD1940 did not significantly attenuate ongoing pain or primary or secondary hyperalgesia compared with placebo. As part of the preclinical evaluation of AZD1940, a microdosing study with PET was conducted to assess brain exposure and the regional distribution of radioactivity within brain that was homogeneous and low in comparison to peripheral organ exposure . Treatment with AZD1940 mediated mild CNS effects, while dose-dependent adverse events related to both CNS and gastrointestinal were reported.…”

“…In vivo metabolism in rats and dogs showed good qualitative agreement with in vitro metabolism. Therefore, rats and dogs were thought to be appropriate species for nonclinical toxicity studies . These data could be useful for characterization of the pharmacokinetic properties of S-777469 and estimation of its pharmacokinetic fate in humans.…”