EXCRETION AND METABOLISM OF THE ANTIHYPERTENSIVE AGENT, RWJ-26240 (MCN-5691) IN DOGS

The excretion and metabolism of a 2-ethynylbenzenealkanamine analog, a ntihypertensive RWJ-26240 (McN-5691), in beagle dogs was investigated, Recoveries of total radioactivity in urine and feces in the 7 days af ter oral administration of C-14-RWJ-26240 (6 mg/kg dose) were 2.8% and 96.8% of the radioactive dose, respectively. Representative plasma, u rine, and fecal samples were pooled and purified for metabolite profil ing, isolation, and identification. Unchanged RWJ-26240 (<19% of the d ose) plus 12 metabolites were isolated and identified from these sampl es using chromatography (TLC, HPLC), spectroscopy (NMR, MS), and deriv atization techniques. Unchanged RWJ-26240 plus identified metabolites accounted for >75% of the sample radioactivity in plasma and feces. Th e formation of RWJ-26240 metabolites can be depicted by the following proposed pathways: 1) N-demethylation, 2) O-demethylation, 3) phenyl h ydroxylation, and 4) N-dealkylation. The first three pathways appeared to be quantitatively important steps which led to the production of f our major metabolites (each >5% of the sample radioactivity). RWJ-2624 0 was extensively metabolized in the dog, and fecal excretion was the major route of elimination of RWJ-26240 and its metabolites.