title: 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 Cmax of 11,308 ng eq. of S-777469/ml at 4.0 h. The AUCinf 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 AUCinf 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.
authors.affiliation: Department of Drug Metabolism & Pharmacokinetics, Research Laboratories for Development and.
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Sekiguchi
authors.forename: Kazuya
authors.initials: K
authors.lastname: Fukumura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hasegawa
authors.forename: Takushi
authors.initials: T
authors.lastname: Kanazu
mesh_terms: D000293:Adolescent; D000328:Adult; D063386:Cannabinoid Receptor Agonists / Q000378:metabolism / Q000493:pharmacokinetics*; D005243:Feces / Q000737:chemistry; D006801:Humans; D008875:Middle Aged; D011728:Pyridones / Q000378:metabolism / Q000493:pharmacokinetics*; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists*; D014556:Urine / Q000737:chemistry
chemical_list: C588309:CNR2 protein, human; D063386:Cannabinoid Receptor Agonists; D011728:Pyridones; D043885:Receptor, Cannabinoid, CB2; C574957:S-777469
keywords: Cannabinoid receptor 2 selective agonist; human mass balance study; metabolite profiling; pharmacokinetics; radiolabeled S-777469