Pharmacokinetics and Metabolism of a Selective Androgen Receptor Modulator in Rats: Implication of Molecular Properties and Intensive Metabolic Profile to Investigate Ideal Pharmacokinetic Characteristics of a Propanamide in Preclinical Study

Abstract

Androgens play important roles in male phenotype development and maintenance of male and female physiology and reproduction (Mooradian et al., 1987). Testosterone and 5␣-dihydrotestosterone are the two main endogenous steroidal androgens involved in reproductive and nonreproductive tissue. Synthesized steroidal androgens have been used as therapeutic agents to treat a broad spectrum of disorders due to androgen deficiency. However, androgen preparations available in the market exhibit severe limitations. Testosterone shows low oral bioavailability, whereas testosterone esters are normally administered via intramuscular injection in oily vehicles, resulting in variable testosterone levels (Handelsman et al., 1990;Wilson, 1996). Although 17␣-alkylated testosterones are orally available, they exhibit a high incidence of hepatotoxicity and less efficacy (Ishak and Zimmerman, 1987). Thus, they are not recommended for long-term androgen therapy. In addition, cross-reactivity occurs between steroidal androgens and/or their in vivo metabolites with steroid receptors other than the androgen receptor, further limiting their clinical use (Wilson et al., 1980;Bhasin and Bremner, 1997). Therefore, there is an urgent need to develop an orally bioavailable drug for patients suffering from a variety of androgen disorders.Nonsteroidal selective androgen receptor modulators (SARMs) possess several advantages over synthesized steroidal androgens, including better receptor selectivity and greater flexibility in structural modification (Zhi and Martinborough, 2001; Yin et al., 2003b,c;Brown, 2004). Our laboratory recently reported the discovery of a series of novel SARMs, with propanamide as a template structure, having potent and tissue-selective in vivo pharmacologic activity (Dalton et al., 1998; Yin et al., 2003a,b,c;Gao et al., 2004;Marhefka et al., 2004;Chen et al., 2005). Among the SARMs discovered in our laboratory, 3-(4-fluorophenoxy)-2-hydroxy-2-methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]-propanamide (denoted hereafter as S-1; Fig. These studies were supported by a grant from the National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK59800-06).Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

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

“…Although N-methylation of amides is rare, the presence of the amide carbonyl and para-nitro substituent on the adjoining aromatic ring makes this an acidic proton and increase the likelihood of N-methylation. Previous in vitro and in vivo metabolism studies with a close structural relative of S-4 demonstrated that N-methylation occurs in the aryl propionamide SARMs (Wu et al, 2006). Furthermore, tandem mass spectrometry spectra of the S4-CH 3 metabolite were similar to those of synthetic standards of N-methylated aryl propionamide SARMs previously reported by our laboratories (Patil et al, 2006).…”

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.…”

Androgen cell signaling pathways involved in neuroprotective actions

“…Similar strategies have been employed in the development of selective estrogen receptor modulators or SERMs including tamoxifen and raloxifene, which exhibit tissue-specific estrogen receptor agonist (e.g., bone, uterus) and antagonist (e.g., breast) actions (Musa et al, 2007). Recently, several new SARMs have been developed that exhibit tissuespecific AR agonist activity (Kearbey et al, 2007;Ostrowski et al, 2007;Wu et al, 2006), although their actions in brain have yet to be reported.…”