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Vol. 304, Issue 3, 1323-1333, March 2003
Division of Pharmaceutics and Pharmaceutical Chemistry, College of
Pharmacy, The Ohio State University, Columbus, Ohio (D.Y., H.X.,
J.T.D.); and Department of Pharmaceutical Sciences, College of
Pharmacy, University of Tennessee, Memphis, Tennessee (Y.H., L.I.K.,
D.D.M.)
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 high-performance 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.
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