Pharmacokinetics ofS-3-(4-acetylamino-phenoxy)-2-hydroxy-2-methyl-N-(4-nitro- 3-trifluoromethyl-phenyl)-propionamide in rats, a non-steroidal selective androgen receptor modulator

Abstract

S-3-(4-acetylamino-phenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethyl-phenyl)-propionamide (also known as S-4) is a non-steroidal selective androgen receptor modulator demonstrating tissue-selective androgenic and anabolic effects. The purpose of the present study was to examine the systemic pharmacokinetics, elimination and oral bioavailability of S-4 in rats.2. Thirty-five male Sprague-Dawley rats weighing approximately 250 g were randomly assigned to one of seven treatment groups. Intravenous doses of 0.5, 1, 10, and 30 mg kg −1 were given via a jugular catheter. Oral doses of 1, 10 and 30 mg kg −1 were administered via gavage. Plasma concentrations were determined using a validated high-performance liquid chromatography or by a high-performance liquid chromatography/mass spectrometry method.3. Clearances ranged between 1.0 and 2.1 ml min −1 kg −1 and varied with dose. The volume of distribution was approximately 0.448 l kg −1 in all treatment groups. Oral bioavailability was also dose dependent, with the lower doses showing complete oral bioavailability. The half-life of S-4 over the dose range tested was between 2.6 and 5.3 h.4. It was demonstrated that S-4 is rapidly absorbed, slowly cleared, and has a moderate volume of distribution in rats. The pharmacokinetics and oral bioavailability of S-4 indicate that it is an excellent candidate for clinical development.

Aryl-Propionamide-Derived Selective Androgen Receptor Modulators: Liquid Chromatography-Tandem Mass Spectrometry Characterization of the in Vitro Synthesized Metabolites for Doping Control Purposes

“…Pharmacokinetic studies of S4 in rats (Kearbey et al, 2004) determined the lack of parent drug in the urine, thus suggesting extensive metabolism, and the more recent in vitro metabolism studies with several enzyme preparations revealed deacetylation, amide hydrolysis, A-ring nitro-reduction, and hydroxylation of aromatic rings as the major phase-I pathways in humans (Gao et al, 2006). In that study, microsomal enzymes were observed to contribute to deacetylation reaction, cytosolic enzymes to hydrolysis, and the role of CYP3A4 enzymes as one of the major phase-I enzymes to catalyze deacetylation, hydrolysis, and oxidative reactions.…”

Nuclear Receptors and Their Selective Pharmacologic Modulators

“…10), was developed using the nonsteroidal androgen antagonist bicalutamide as the lead compound (Gao et al, 2005). Pharmacokinetics studies demonstrated that S-4 is rapidly absorbed, slowly cleared, and has a moderate volume of distribution in rats (Kearbey et al, 2004). S-4 also showed in vivo both 740 androgenic and anabolic activity that is tissue selective.…”

Preclinical Pharmacology of a Nonsteroidal Ligand for Androgen Receptor-Mediated Imaging of Prostate Cancer

“…Therefore, unlike steroidal analogs, low-affinity plasma protein binding to albumin is unlikely to compete significantly with high-affinity target tissue binding sites. In addition, we performed in vivo studies with a number of compounds, with similar chemical structures demonstrating their favorably pharmacokinetic and pharmacodynamic properties (Yin et al, 2003a;Kearbey et al, 2004;Gao et al, 2005) suggesting that S-26 will be efficacious in vivo.…”