Characterization of the in Vitro Metabolism of Selective Androgen Receptor Modulator Using Human, Rat, and Dog Liver Enzyme Preparations

Gao, Wenqing; Wu, Zhentian; Bohl, Casey E.; Yang, Jun; Miller, Duane D.; Dalton, James T.

doi:10.1124/dmd.105.007112

Cited by 32 publications

(36 citation statements)

References 18 publications

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“…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.…”

Section: Identification Of Major Metabolites Of S-26 In Rat Urine Andsupporting

confidence: 58%

“…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.…”

Section: Discussionmentioning

confidence: 89%

“…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.…”

Section: Discussionmentioning

confidence: 99%

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

Yang

Wu²,

Wu³

et al. 2009

Int J Oncol

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Abstract. Knowledge of the presence and extent of disease plays a major role in clinical management of prostate cancer, as it provides meaningful information as to which therapy to choose and who might benefit from this therapy. The wide expression of androgen receptor (AR) in primary and metastatic prostate tumors offers a cellular target for receptormediated imaging of prostate cancer. In our previous study, a non-steroidal AR ligand, S-26 [S-3-(4-fluorophenoxy)-2-hydroxy-2-methyl-N-(4-cyano-3-iodophenyl)-propionamide] showed promising in vitro pharmacological properties as an AR-mediated imaging agent, with high AR binding affinity and AR specificity. The overall goal of this study was to characterize the in vivo metabolic and biodistribution profile of S-26 in rats. Non-compartmental pharmacokinetic analysis of S-26 in rat plasma showed that clearance (CL), volume of distribution (Vd ss ), and half-life (T 1/2 ) of S-26 were 0.30±0.07 l/h/kg, 1.44±0.33 l/kg, and 4 h, respectively, after intravenous (i.v.) administration. Dose proportionality (1, 10 and 30 mg/kg) studies suggested that the pharmacokinetics of S-26 are dose-independent. The plasma concentrations of all 3 doses were further simultaneously fitted with a two-compartmental model and the results were similar to those obtained from non-compartmental analysis. Biodistribution studies using 125 I-labeled S-26 indicated that it did not specifically target AR-rich tissue (e.g. prostate). A substantial amount of radioactivity recovered from thyroid gland indicated the release of free iodine. In metabolism studies, unchanged S-26 and its metabolites were detected in rat urine and fecal samples. Oxidation, de-iodination, hydrolysis, and sulfate conjugation were the major metabolic pathways of S-26 in rats, with deiodination representing a unique metabolic pathway of S-26 among other selective androgen receptor modulators. In conclusion, the extensive plasma clearance and de-iodination of S-26 likely contribute to its lack of AR tissue selectivity in vivo. Future studies using metabolically stable ligands with less lipophilicity and higher AR binding affinity may represent a promising and rational approach for AR-mediated imaging.

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Section: Identification Of Major Metabolites Of S-26 In Rat Urine Andsupporting

confidence: 58%

Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

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

Yang

Wu²,

Wu³

et al. 2009

Int J Oncol

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“…Our previous in vitro metabolism studies (Gao et al, 2006b) have identified species differences between rats and dogs in the metabolism of S-4. Thus, we also further characterized and compared the metabolic profiles of S-4 in these two species.…”

Section: S-3-(4-acetylamino-phenoxy)-2-hydroxy-2-methyl-n-(4-nitro-3-mentioning

confidence: 99%

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

Perera¹,

Yin²,

Wu³

et al. 2006

Drug Metab Dispos

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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...

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“…S1, S4, and C6 share similar metabolic labile sites, including the amide bond and the A-ring nitro group, as amide bond hydrolysis and nitro reduction were identified as the major metabolic pathway (Fig. 6) both in vivo (data not published) and in vitro (60,61). All three derivatives are eliminated exclusively through hepatic metabolism.…”

Section: Bothmentioning

confidence: 99%

Pharmacokinetics and Pharmacodynamics of Nonsteroidal Androgen Receptor Ligands

2006

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Testosterone and structurally related anabolic steroids have been used to treat hypogonadism, muscle wasting, osteoporosis, male contraception, cancer cachexia, anemia, and hormone replacement therapy in aging men or age-related frailty; while antiandrogens may be useful for treatment of conditions like acne, alopecia (male-pattern baldness), hirsutism, benign prostatic hyperplasia (BPH) and prostate cancer. However, the undesirable physicochemical and pharmacokinetic properties of steroidal androgen receptor (AR) ligands limited their clinical use. Nonsteroidal AR ligands with improved pharmacological and pharmacokinetic properties have been developed to overcome these problems. This review focuses on the pharmacokinetics, metabolism, and pharmacology of clinically used and emerging nonsteroidal AR ligands, including antagonists, agonists, and selective androgen receptor modulators.

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Characterization of the in Vitro Metabolism of Selective Androgen Receptor Modulator Using Human, Rat, and Dog Liver Enzyme Preparations

Cited by 32 publications

References 18 publications

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

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

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

Pharmacokinetics and Pharmacodynamics of Nonsteroidal Androgen Receptor Ligands

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