Abstract
S-1 [3-(4-fluorophenoxy)-2-hydroxy-2-methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]-propanamide] is one member of a series of potent selective androgen receptor modulators (SARMs) that are being explored and developed for androgen-dependent diseases. Recent studies showed that S-1 holds great promise as a novel therapeutic agent for benign hyperplasia [W. Gao, J. D. Kearbey, V. A. Nair, K. Chung, A. F. Parlow, D. D. Miller, and J. T. Dalton (2004) Endocrinology 145:5420–5428]. We examined the pharmacokinetics and metabolism of S-1 in rats as a component of our preclinical development of this compound and continued interest in structure-activation relationships for SARM action. Forty male Sprague-Dawley rats were randomly assigned to treatment groups and received either an i.v. or a p.o. dose of S-1 at a dose level of 0.1, 1, 10, or 30 mg/kg. S-1 demonstrated a low clearance (range, 3.6–5.2 ml/min/kg), a moderate volume of distribution (range, 1460–1560 ml/kg), and a terminal half-life ranging from 3.6 to 5.2 h after i.v. doses. The oral bioavailability of S-1 ranged from 55% to 60%. Forty phase I and phase II metabolites of S-1 were identified in the urine and feces of male Sprague-Dawley rats dosed at 50 mg/kg via the i.v. route. The two major urinary metabolites of S-1 were a carboxylic acid and a sulfate-conjugate of 4-nitro-3-trifluoromethylphenylamine. Phase I metabolites arising from A-ring nitro reduction to an aromatic amine and B-ring hydroxylation were also identified in the urinary and fecal samples of rats. Furthermore, a variety of phase II metabolites through sulfation, glucuronidation, and methylation were also found. These studies demonstrate that S-1 is rapidly absorbed, slowly cleared, moderately distributed, and extensively metabolized in rats.
Footnotes
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These studies were supported by a grant from the National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK59800-06).
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.105.006643.
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ABBREVIATIONS: SARM, selective androgen receptor modulator; S-1, 3-(4-fluorophenoxy)-2-hydroxy-2-methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]-propanamide; S-4, 3-[4-(acetylamino)phenoxy]-2-hydroxy-2-methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]-propanamide); C-6, 3-(4-chloro-3-fluorophenoxy)-2-hydroxy-2-methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]-propanamide; M-1, 3-(4-fluorophenoxy)-2-hydroxy-2-methylpropanoic acid; PEG-300, polyethylene glycol-300; DMSO, dimethyl sulfoxide; AUC, area under the plasma concentration-time curve; AUMC, area under the first moment of the plasma concentration-time curve; Cmax, maximal drug plasma concentration; Tmax, time to reach the maximal drug concentration (at the Cmax); Vss, steady-state volume of distribution; CL, clearance; MRT, mean residence time; V, volume of distribution; HPLC, high-performance liquid chromatography; LC-MS, liquid chromatography-mass spectrometry.
- Received July 21, 2005.
- Accepted December 27, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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