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.
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.106.009985.
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ABBREVIATIONS: SARM, selective androgen receptor modulator; AUC, area under 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; V, volume of distribution; CL, clearance; AUMC, area under the first moment of the plasma concentration-time curve; PEG 300, polyethylene glycol 300; MRT, mean residence time; HPLC, high-performance liquid chromatography; LC/MS, liquid chromatography/mass spectrometry;
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↵1 Current affiliation: GTx Inc., Memphis, Tennessee.
- Received February 27, 2006.
- Accepted June 29, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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