Abstract 1311: Disposition and biotransformation of [14C]-radiolabeled CS-7017 in healthy male subjects
Authors: Bathala Mohinder , Uchiyama Minoru , Koda Hiroko , He Ling , Pickersgill Fraser , Koyama Kumiko , Zahir Hamim , Iwabuchi Haruo , Izumi Takashi , Tokui Taro 
Published: June 2012

Abstract
Background: CS-7017 is a novel, oral, highly potent and selective peroxisome proliferator-activated receptor gamma agonist with demonstrated anticancer activity in preclinical models. Currently, CS-7017 is in phase 2 trials for the treatment of non-small cell lung and colorectal cancer. CS-7017 disposition and biotransformation were investigated in healthy male subjects following oral administration of [14C]-radiolabeled CS-7017.
Methods: Blood, plasma, urine, and fecal samples were collected and analyzed for radioactive levels to determine CS-7017 disposition following a single 0.5 mg oral dose containing approximately 50 µCi of [14C]-radiolabeled CS-7017 in 6 healthy male subjects. Metabolite separation, identification, and quantification were performed using radio/HPLC followed by LC-ESI/MS and LC-MS/MS. Plasma samples were also analyzed using LC-MS/MS for CS-7017 and by accelerator mass spectrometry for metabolite profiling.
Results: CS-7017 was rapidly absorbed (plasma Tmax: 1.52 h) and steadily eliminated following oral administration. The majority of radioactivity was eliminated in feces (∼70% vs ∼20% in urine). In blood, the radioactivity was mainly distributed in plasma with little or no association with blood cells, as indicated by a blood to plasma ratio of 0.5. The parent molecule is the main circulating analyte in plasma contributing 60-70% of the total exposure. R-239457 (dearyl form) and its sulphate were the two highest circulating metabolites contributing 4.5% and 6.3% of the total radioactivity at 12 h post-dose, respectively. Several other radioactive peaks (∼12) were detected in plasma at a low level (&lt;2.5%). In both urine and feces, several metabolites such as N-glucuronide of CS-7017, and R-239457 and its sulphate and glucuronide forms were observed, whereas little or no parent CS-7017 was detected.
Conclusion: CS-7017 was rapidly absorbed and steadily eliminated with the parent molecule contributing the majority of the exposure; this indicates that CS-7017 itself contributes toward in vivo pharmacological activity. Traces of the parent molecule in urine and feces indicate that the majority of the drug is eliminated by metabolism. Therefore, CS-7017 exposure may be impacted by hepatic impairment, but may not be significantly changed in subjects with impaired renal function as renal excretion contributes to a relatively low proportion of clearance (∼20%). Based on the metabolite profiles, the metabolic routes in human and animals (rats and monkeys) are similar. The two highest metabolites detected in human plasma were also present in the plasma of at least one of the preclinical toxicology species, therefore, safety concerns raised by the metabolites would be minimal in humans.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1311. doi:10.1158/1538-7445.AM2011-1311