title: 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.
authors.affiliation: Drug Metabolism & Pharmacokinetics, Drug Developmental Research Laboratories , Shionogi & Co., Ltd., 1-1, Futaba-cho 3-chome, Toyonaka, Osaka, 561-0825 , Japan.
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Sekiguchi
authors.forename: Takushi
authors.initials: T
authors.lastname: Kanazu
authors.forename: Masaharu
authors.initials: M
authors.lastname: Takeuchi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hasegawa
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Yamaguchi
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002250:Carbon Radioisotopes / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008297:Male; D015394:Molecular Structure; D011728:Pyridones / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists*; D013045:Species Specificity; D053719:Tandem Mass Spectrometry
chemical_list: C588309:CNR2 protein, human; D002250:Carbon Radioisotopes; D011728:Pyridones; D043885:Receptor, Cannabinoid, CB2; C574957:S-777469