Pharmacokinetics and metabolism of a selective androgen receptor modulator in rats: implication of molecular properties and intensive metabolic profile to investigate ideal pharmacokinetic characteristics of a propanamide in preclinical study.
S-1 [3-(4-fluorophenoxy)-2-hydroxy-2-methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]-propanamide] is one member of a series of potent selective androgen receptor modulators (SARMs) that are being explored and developed for androgen-dependent diseases. Recent studies showed that S-1 holds great promise as a novel therapeutic agent for benign hyperplasia [W. Gao, J. D. Kearbey, V. A. Nair, K. Chung, A. F. Parlow, D. D. Miller, and J. T. Dalton (2004) Endocrinology 145:5420-5428]. We examined the pharmacokinetics and metabolism of S-1 in rats as a component of our preclinical development of this compound and continued interest in structure-activation relationships for SARM action. Forty male Sprague-Dawley rats were randomly assigned to treatment groups and received either an i.v. or a p.o. dose of S-1 at a dose level of 0.1, 1, 10, or 30 mg/kg. S-1 demonstrated a low clearance (range, 3.6-5.2 ml/min/kg), a moderate volume of distribution (range, 1460-1560 ml/kg), and a terminal half-life ranging from 3.6 to 5.2 h after i.v. doses. The oral bioavailability of S-1 ranged from 55% to 60%. Forty phase I and phase II metabolites of S-1 were identified in the urine and feces of male Sprague-Dawley rats dosed at 50 mg/kg via the i.v. route. The two major urinary metabolites of S-1 were a carboxylic acid and a sulfate-conjugate of 4-nitro-3-trifluoromethylphenylamine. Phase I metabolites arising from A-ring nitro reduction to an aromatic amine and B-ring hydroxylation were also identified in the urinary and fecal samples of rats. Furthermore, a variety of phase II metabolites through sulfation, glucuronidation, and methylation were also found. These studies demonstrate that S-1 is rapidly absorbed, slowly cleared, moderately distributed, and extensively metabolized in rats.
Wu
Di
D
Division of Pharmaceutics, College of Pharmacy, The Ohio State University, 500 West 12 Ave., Columbus, OH 43210, USA.
Wu
Zengru
Z
Yang
Jun
J
Nair
Vipin A
VA
Miller
Duane D
DD
Dalton
James T
JT
D000284:Administration, Oral; D000577:Amides / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D000728:Androgens / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D000814:Aniline Compounds / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D000818:Animals; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D004353:Drug Evaluation, Preclinical; D008658:Inactivation, Metabolic; D007275:Injections, Intravenous; D008297:Male; D013058:Mass Spectrometry; D015394:Molecular Structure; D051381:Rats; D017207:Rats, Sprague-Dawley; D011944:Receptors, Androgen / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
C510278:3-(4-fluorophenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-(trifluoromethyl)phenyl)propanamide; D000577:Amides; D000728:Androgens; D000814:Aniline Compounds; D011944:Receptors, Androgen