title: Absorption, Distribution, Metabolism, and Excretion of the Androgen Receptor Inhibitor Enzalutamide in Rats and Dogs.
abstract: OBJECTIVE
  Enzalutamide is an androgen receptor inhibitor that has been approved in several countries. Absorption, distribution, metabolism, and excretion (ADME) data in animals would facilitate understanding of the efficacy and safety profiles of enzalutamide, but little information has been reported in public. The purpose of this study was to clarify the missing ADME profile in animals.
  
  
  METHODS
  ADME of14C-enzalutamide after oral administration as Labrasol solution were investigated in non-fasted male Sprague-Dawley rats and beagle dogs.
  
  
  RESULTS
  Plasma concentrations of14C-enzalutamide peaked in rats and dogs at 6-8 h after a single oral administration. In most tissues, radioactivity concentration peaked at 4 h after administration. Excluding the gastrointestinal tract, tissues with the highest concentration of radioactivity were liver, fat, and adrenal glands. The tissue concentrations of radioactivity declined below the limit of quantitation or <0.89 % of maximum concentration by 168 h post-dose. Two known metabolites (M1 and M2) and at least 15 novel possible metabolites were detected in this study. M1 was the most abundant metabolite in both rats and dogs. Unchanged drug was a minor component in excreta. In intact rats, the mean urinary and fecal excretion of radioactivity accounted for 44.20 and 49.80 % of administered radioactivity, respectively. In intact dogs, mean urinary and fecal excretion was 62.00 and 22.30 % of the administered radioactivity, respectively.
  
  
  CONCLUSIONS
  Rapid oral absorption was observed in rats and dogs when14C-enzalutamide was administered as Labrasol solution. Tissue distribution in rats was clarified. The elimination of enzalutamide is mediated primarily by metabolism. Species differences were observed in excretion route.
authors: Analysis and Pharmacokinetics Research Laboratories, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki, 305-8585, Japan. yoshiaki.ohtsu@zoho.com.
authors: Yoshiaki
authors: http://orcid.org/0000-0003-0494-5717
authors: Y
authors: Ohtsu
authors: Clinical Pharmacology and DMPK, Medivation, Inc., 525 Market Street, 36th Floor, San Francisco, CA, 94105, USA.
authors: Jacqueline A
authors: JA
authors: Gibbons
authors: Analysis and Pharmacokinetics Research Laboratories, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki, 305-8585, Japan.
authors: Katsuhiro
authors: K
authors: Suzuki
authors: Covance Laboratories Inc., 3301 Kinsman Boulevard, Madison, WI, 53704, USA.
authors: Michael E
authors: ME
authors: Fitzsimmons
authors: Sekisui Medical Co., Ltd., 2117 Muramatsu, Tokai, Naka, Ibaraki, 319-1182, Japan.
authors: Kohei
authors: K
authors: Nozawa
authors: Analysis and Pharmacokinetics Research Laboratories, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki, 305-8585, Japan.
authors: Hiroshi
authors: H
authors: Arai
mesh_terms: D000284:Administration, Oral; D059002:Androgen Receptor Antagonists / Q000097:blood* / Q000378:metabolism / Q000652:urine*; D000818:Animals; D001549:Benzamides; D001646:Bile / Q000737:chemistry; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005243:Feces / Q000737:chemistry; D065669:Hepatobiliary Elimination; D008297:Male; D008657:Metabolic Clearance Rate; D009570:Nitriles; D065568:Oral Mucosal Absorption; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000652:urine; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D014018:Tissue Distribution
chemical_list: D059002:Androgen Receptor Antagonists; D001549:Benzamides; D009570:Nitriles; D010669:Phenylthiohydantoin; C540278:enzalutamide