Received for publication June 27, 2002.
Revised July 31, 2002.
Accepted for publication October 3, 2002.

Pharmacology, Pharmacokinetics, and Metabolism of Acetothiolutamide, A Novel Nonsteroidal Agonist for the Androgen Receptor

Abstract

The present studies characterized the in vitro androgen receptor (AR) binding affinity, in vitro and in vivo pharmacologic 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 co-transfection assay. Acetothiolutamide displayed high AR binding affinity (Ki = 4.9 ± 0.2 nM) and full agonist activity in these 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 (CL about 45 mL/min/kg) in a concentration- independent manner after IV dosing. Acetothiolutamide was completely absorbed following 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 HPLC-MS. The structures of major metabolites were elucidated with LC-MS/MS. After IV 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.

Key words: androgen, mass spectrometry, metabolism, pharmacokinetics, pharmacology, receptor

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