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First published on November 4, 2005; DOI: 10.1124/dmd.105.007112

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Received for publication September 1, 2005.
Revised October 25, 2005.
Accepted for publication November 2, 2005.

Characterization of the In vitro Metabolism of Selective Androgen Receptor Modulator (SARM) Using Human, Rat and Dog Liver Enzyme Preparations

Wenqing Gao 1, Zengru Wu 1, Casey E Bohl 1, Jun Yang 1, Duane D Miller 2, James T. Dalton 1*

1 The Ohio State University 2 University of Tennessee

* Address correspondence to: E-mail: dalton.1{at}osu.edu

Abstract

Compound S4 is a novel nonsteroidal selective androgen receptor modulator (SARM) that demonstrates tissue-selective androgenic and anabolic effects. The purpose of this in vitro study was to identify the phase I metabolites, potential species differences in metabolism, and the cytochrome P450s (CYPs) involved in the phase I metabolism of S4 using 14C-S4, recombinant CYPs and other liver enzyme preparations from human, rat, and dog. The major phase I metabolism pathways of S4 in humans were identified as: deacetylation of the B-ring acetamide group, hydrolysis of the amide bond, reduction of the A-ring nitro group, and oxidation of the aromatic rings, with deacetylation being the predominant pathway observed with most of the enzyme preparations tested. Among the major human CYP enzymes tested, CYP3A4 appeared to be one of the major phase I enzymes that could be responsible for the phase I metabolism of S4 (Km=16.1 µM, Vmax=1.6 pmole/(pmole·min)) in human, and mainly catalyzed the deacetylation, hydrolysis, and oxidation of S4. In human, the cytosolic enzymes mainly catalyzed the hydrolysis reaction, while the microsomal enzymes primarily catalyzed the deacetylation reactions. Similar phase I metabolic profiles were observed in rats and dogs as well, except for that amide bond hydrolysis seemed to occur more rapidly in rats. In summary, these results showed that the major phase I reaction of S4 in human, rat, and dog is acetamide group deacetylation.


Key words: acetyltransferases, human CYP enzymes, liver microsomes, metabolite identification, nuclear receptors


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