TY - JOUR T1 - In Vivo Metabolism and Final Disposition of a Novel Nonsteroidal Androgen in Rats and Dogs JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1713 LP - 1721 DO - 10.1124/dmd.106.009985 VL - 34 IS - 10 AU - Minoli A. Perera AU - Donghua Yin AU - Di Wu AU - Kenneth K. Chan AU - Duane D. Miller AU - James Dalton Y1 - 2006/10/01 UR - http://dmd.aspetjournals.org/content/34/10/1713.abstract N2 - Compound S-4 (S-3-(4-acetylamino-phenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethyl-phenyl)-propionamide) is a novel nonsteroidal androgen agonist that mimics many of the beneficial pharmacologic effects of testosterone with lesser effects on the prostate. S-4 demonstrated high androgen receptor binding affinity as well as anabolic specificity during in vivo pharmacologic studies in rats, identifying it as the first member of a new class of selective androgen receptor modulators. The purpose of these studies was to determine the pharmacokinetics and metabolism of S-4 in dogs. S-4 showed linear pharmacokinetics after both intravenous (i.v.) and oral (p.o.) administrations at pharmacologically relevant doses, with a mean clearance of 4.6 ml/min/kg and a mean half-life of about 200 min. It is interesting that dose-dependent oral bioavailability was seen. However, at pharmacologically relevant doses, the oral bioavailability of S-4 was 91%. Species differences were observed in S-4 metabolism; the major metabolic pathway for S-4 in dogs was deacetylation of the B-ring acetamide group and reduction of the A-ring nitro group, whereas the major metabolic pathway for S-4 in rats was hydrolysis on the amide bond and reduction of the A-ring nitro group. In addition, oxidative metabolites and phase II metabolites were identified in both rats and dogs. These studies demonstrate that S-4 maintains its promising pharmacokinetic properties in dogs (i.e., high oral bioavailability and linear kinetics) and is largely eliminated via hepatic metabolism by both phase I and phase II enzymes. The American Society for Pharmacology and Experimental Therapeutics ER -