Pharmacology, pharmacokinetics, and metabolism of acetothiolutamide, a novel nonsteroidal agonist for the androgen receptor

Donghua Yin, Huiping Xu, Yali He, Leonid I. Kirkovsky, Duane Miller, James T. Dalton

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

The present study characterized the in vitro androgen receptor (AR) binding affinity, in vitro and in vivo pharmacological activity, and in vivo pharmacokinetics and metabolism of acetothiolutamide, a nonsteroidal AR ligand. AR binding was determined by a competitive binding assay. In vitro AR agonist activity was examined by a cotransfection assay. Acetothiolutamide displayed high AR binding affinity (Ki = 4.9 ± 0.2 nM) and full agonist activity in the in vitro studies. Next, the androgenic, anabolic, and antiandrogenic activity of acetothiolutamide was evaluated in a castrated immature rat model. In this animal model, acetothiolutamide exhibited an overall negligible androgenic effect, but a statistically significant anabolic effect at high subcutaneous doses. Also, acetothiolutamide demonstrated a noticeable antiandrogenic effect in castrated rats supplemented with testosterone propionate. To understand the causes for the observed disparity between in vitro and in vivo activities, pharmacokinetics and metabolism of acetothiolutamide were studied in male Sprague-Dawley rats. Acetothiolutamide was rapidly cleared from rat plasma (clearance of about 45 ml/min/kg) in a concentration-independent manner after i.v. dosing. Acetothiolutamide was completely absorbed after subcutaneous administration, but not bioavailable after oral dose. In the metabolism study, the unchanged molecule and its metabolites in urine and fecal samples were detected by highperformance liquid chromatography-mass spectrometry. The structures of major metabolites were elucidated with liquid chromatography-tandem mass spectrometry. After i.v. administration, acetothiolutamide was excreted in urine and feces as unchanged drug and a variety of metabolites. Oxidation, hydrolysis, and sulfate conjugation of phase I metabolites were the major metabolic pathways of acetothiolutamide in rats. Overall, the high plasma clearance of acetothiolutamide, due to its extensive hepatic metabolism, likely contributed to its lack of androgenic activity in vivo.

Original languageEnglish (US)
Pages (from-to)1323-1333
Number of pages11
JournalJournal of Pharmacology and Experimental Therapeutics
Volume304
Issue number3
DOIs
StatePublished - Mar 1 2003

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Androgens
Pharmacokinetics
Pharmacology
Androgen Receptors
Liquid Chromatography
acetothiolutamide
Urine
Testosterone Propionate
Anabolic Agents
Competitive Binding
Tandem Mass Spectrometry
Metabolic Networks and Pathways
Feces
Sulfates
Sprague Dawley Rats
Mass Spectrometry
Hydrolysis
Animal Models
In Vitro Techniques
Ligands

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

Cite this

Pharmacology, pharmacokinetics, and metabolism of acetothiolutamide, a novel nonsteroidal agonist for the androgen receptor. / Yin, Donghua; Xu, Huiping; He, Yali; Kirkovsky, Leonid I.; Miller, Duane; Dalton, James T.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 304, No. 3, 01.03.2003, p. 1323-1333.

Research output: Contribution to journalArticle

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