In vivo metabolism and final disposition of a novel nonsteroidal androgen in rats and dogs.
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.
Perera
Minoli A
MA
Division of Pharmaceutics, College of Pharmacy, The Ohio State University, 500 West 12th Ave., Columbus, OH 43210, USA.
Yin
Donghua
D
Wu
Di
D
Chan
Kenneth K
KK
Miller
Duane D
DD
Dalton
James
J
D000081:Acetamides / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D000284:Administration, Oral; D000627:Aminophenols / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D000728:Androgens / Q000097:blood / Q000493:pharmacokinetics / Q000652:urine; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D002250:Carbon Radioisotopes; D002853:Chromatography, Liquid / Q000379:methods; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005243:Feces / Q000737:chemistry; D006207:Half-Life; D007275:Injections, Intravenous; D008099:Liver / Q000378:metabolism; D008297:Male; D013058:Mass Spectrometry / Q000379:methods; D008657:Metabolic Clearance Rate; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity
D000081:Acetamides; D000627:Aminophenols; D000728:Androgens; D002250:Carbon Radioisotopes; C492992:andarine