Received for publication March 8, 2006.
Revised June 29, 2006.
Accepted for publication June 29, 2006.

IN VIVO METABOLISM AND FINAL DISPOSITION OF A NOVEL NONSTEROIDAL ANDROGEN IN RATS AND DOGS

Abstract

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 (AR) 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 (SARMs). 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 (IV) and oral (PO) administrations at pharmacologically relevant doses, with a mean clearance of 4.6 ml/min/kg and a mean half-life of about 200 minutes. Interestingly, 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, while 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.

Key words: bioavailability, HPLC, mass spectrometry, metabolite identification, nuclear receptors, pharmacokinetics, reductases