In vivo metabolism and final disposition of a novel nonsteroidal androgen in rats and dogs

Minoli A. Perera, Donghua Yin, Di Wu, Kenneth K. Chan, Duane Miller, James Dalton

Research output: Contribution to journalArticle

15 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1713-1721
Number of pages9
JournalDrug Metabolism and Disposition
Volume34
Issue number10
DOIs
StatePublished - Sep 27 2006

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Pharmacokinetics
Metabolism
Androgens
Rats
Androgen Receptors
Dogs
Biological Availability
Metabolites
Metabolic Networks and Pathways
Enzyme kinetics
Amides
Modulators
Testosterone
Hydrolysis
Oral Administration
Half-Life
Prostate
Enzymes
Liver

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmaceutical Science

Cite this

In vivo metabolism and final disposition of a novel nonsteroidal androgen in rats and dogs. / Perera, Minoli A.; Yin, Donghua; Wu, Di; Chan, Kenneth K.; Miller, Duane; Dalton, James.

In: Drug Metabolism and Disposition, Vol. 34, No. 10, 27.09.2006, p. 1713-1721.

Research output: Contribution to journalArticle

Perera, Minoli A. ; Yin, Donghua ; Wu, Di ; Chan, Kenneth K. ; Miller, Duane ; Dalton, James. / In vivo metabolism and final disposition of a novel nonsteroidal androgen in rats and dogs. In: Drug Metabolism and Disposition. 2006 ; Vol. 34, No. 10. pp. 1713-1721.
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