In Vivo Metabolism and Final Disposition of a Novel Nonsteroidal Androgen in Rats and Dogs

Abstract

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 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.Testosterone, an endogenous ligand for the androgen receptor, plays important and diverse physiological roles in several different organ systems, including muscle and bone (George and Wilson, 1986;Hiort, 2002). Testosterone and related anabolic steroids are used clinically as replacement therapy for primary or hypogonadotropic hypogonadism, delayed puberty, anemia, or muscle wasting conditions (Mooradian et al., 1987;Bagatell and Bremner, 1996). However, there are many disadvantages associated with testosterone and anabolic steroid therapy (Basaria and Dobs, 1999). First, current testosterone preparations can only be administered via intramuscular injections (Snyder and Lawrence, 1980). Although 17␣-alkylated androgens were developed for oral administration, they are associated with hepatic toxicity and are less efficacious; hence, they are not recommended for long-term androgen therapy (Swerdloff and Wang, 2002). Second, testosterone injections produce large fluctuations in testosterone plasma concentrations, which may lead to adverse effects such as hepatoxicity, blood pressure effects, and gynecomastia (Heywood et al., 1977;Negro-Vilar, 1999). Third, current steroidal preparations demonstrate equal anabolic and androgenic activity (i.e., they are not tissue-selective). The nonselective nature of testosterone and its derivatives, poor pharmacokinetic properties, and toxicities have led to the search for androgens with improved pro...

Pharmacokinetics, biodistribution and metabolism of a novel selective androgen receptor modulator designed for prostate cancer imaging

“…4A shows the proposed fragmentation ions of S-26. Similar metabolic pathways of SARMs were reported also previously by our laboratory (23)(24)(25). The product ion at m/z 299 corresponds to a cleavage of the bond between the chiral carbon and methylene carbon with loss of a methyl group.…”

“…Among all tissues, the thyroid gland accumulated the highest percentage of radioactivity at all three time points, suggesting that S-26 was extensively de-iodinated in vivo, which was further confirmed by our metabolism studies using rat urine and feces. The deiodination of S-26 represented a different metabolic pathway of SARMs comparing to the metabolism studies previously reported by our laboratory (23)(24)(25). The high accumulation of radioactivity by GI tract and a large proportion of radioactivity in urine are also indications of release of free iodine from the parent drug in vivo.…”

“…Fat also represents a relatively high uptake of radioactivity in tissue, which might be due to the high lipophilicity (i.e., log P=4.78) of S-26. However, it is important to note that rats appear to be unique in terms of their greater ability for amide bond cleavage of bicalutamide and the aryl propionamide SARMs as compared to dogs and humans (23)(24)(25)33). Therefore, rats may not represent an ideal model for the feasibility studies of radiolabeled SARMs.…”

Selective androgen receptor modulators: comparative excretion study of bicalutamide in bovine urine and faeces

“…[7] While in Europe, growth promoters have been banned for use in food-producing animals since 1988 (Council Directive 88/146/EEC prohibiting the use livestock farming of certain substances having a hormonal action 1988), strategies to detect potential SARMs misuse in livestock production are urgently required to guarantee consumers of food from animal origin free of any residues of such compounds. Furthermore, and because it has been demonstrated in different species that SARMs were eliminated in the faeces, [9,[22][23][24][25][26][27][28][29][30] the present work aims at studying faeces as an alternative interesting biological matrix to detect these substances in livestock. [18,19] Since these compounds have recently emerged, they have not been investigated a lot.…”

“…We therefore propose in this study to investigate further SARMs elimination and metabolism in bovine. Furthermore, and because it has been demonstrated in different species that SARMs were eliminated in the faeces, [9,[22][23][24][25][26][27][28][29][30] the present work aims at studying faeces as an alternative interesting biological matrix to detect these substances in livestock. Faeces is indeed an easy-to-collect matrix and its relevance in livestock for detecting some residues or metabolites of growth promoters has already been demonstrated.…”