RT Journal Article
SR Electronic
T1 Excretion and Metabolism of the Antihypertensive Agent, RWJ-26240 (McN-5691) in Dogs
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 115
OP 125
VO 26
IS 2
A1 W. N. Wu
A1 J. A. Masucci
A1 G. W. Caldwell
A1 J. R. Carson
YR 1998
UL http://dmd.aspetjournals.org/content/26/2/115.abstract
AB The excretion and metabolism of a 2-ethynylbenzenealkanamine analog, antihypertensive RWJ-26240 (McN-5691), in beagle dogs was investigated. Recoveries of total radioactivity in urine and feces in the 7 days after oral administration of14C-RWJ-26240 (6 mg/kg dose) were 2.8% and 96.8% of the radioactive dose, respectively. Representative plasma, urine, and fecal samples were pooled and purified for metabolite profiling, isolation, and identification. Unchanged RWJ-26240 (<19% of the dose) plus 12 metabolites were isolated and identified from these samples using chromatography (TLC, HPLC), spectroscopy (NMR, MS), and derivatization techniques. Unchanged RWJ-26240 plus identified metabolites accounted for >75% of the sample radioactivity in plasma and feces. The formation of RWJ-26240 metabolites can be depicted by the following proposed pathways: 1) N-demethylation, 2)O-demethylation, 3) phenyl hydroxylation, and 4)N-dealkylation. The first three pathways appeared to be quantitatively important steps which led to the production of four major metabolites (each >5% of the sample radioactivity). RWJ-26240 was extensively metabolized in the dog, and fecal excretion was the major route of elimination of RWJ-26240 and its metabolites. The American Society for Pharmacology and Experimental Therapeutics