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

In vivo metabolism and final disposition of a novel nonsteroidal androgen in rats and dogs. Research Abstract Details 

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In vivo metabolism and final disposition of a novel nonsteroidal androgen in rats and dogs. Abstract Text:

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

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.

In vivo metabolism and final disposition of a novel nonsteroidal androgen in rats and dogs. Publishing Authors By Initials

MA Perera,D Yin,D Wu,KK Chan,DD Miller,J Dalton,

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In vivo metabolism and final disposition of a novel nonsteroidal androgen in rats and dogs. Journal Published:

PUBLICATION TYPE: Research Support, N.I.H., Extr

Journal: Drug metabolism and disposition: the biological fa

VOLUME: 34

Page Numbers: 1713-21

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ISSN: 0090-9556

DAY: 30

MONTH: 06

YEAR: 2006

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

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LANGUAGE: eng

NlmUniqueID: 9421550

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AFFILIATION: Division of Pharmaceutics, College of Pharmacy, The Ohio State University, 500 West 12th Ave., Columbus, OH 43210, USA.

Country: United States

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MEDLINETA: Drug Metab Dispos

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