METABOLISM OF MK-499, A CLASS-III ANTIARRHYTHMIC AGENT, IN RATS AND DOGS

MK-499 [(+)-N-[1'-(6-cyano-1, 2, 3, enzopyran-2,4'-piperidin)-6-yl]met hanesulfonamide] monohydrochloride is an investigational class III ant iarrhythmic agent for treatment of malignant ventricular tachyarrhythm ias. The disposition of [H-3]MK-499 and [C-14]MK-499 was studied in ra ts and dogs after oral and iv administration. MK-499 was concentrated in organs of excretion and the heart. In the rat, urinary radioactivit y elimination values after IV (0.5 mg/kg) and oral (6.25 mg/kg) doses were 21 +/- 3% and 10 +/- 2%, respectively, Corresponding fecal recove ries were 68 +/- 6% and 78 +/- 7%, Similar results were found after co rresponding doses of [C-14]MK-499. In dogs, urine and feces accounted for 16 +/- 3% and 75 +/- 4% of recovered radioactivity after a [H-3]MK -499 IV dose (0.1 mg/kg), Corresponding recoveries after an oral dose (1 mg/kg) were 12 +/- 2% and 76 +/- 3%. Biliary (0-24 hr) excretion ac counted for 39 +/- 5% and 41 +/- 18% of [H-3] and [C-14] Oral doses in rats, respectively. Dogs excreted 34% of [H-3] oral dose in (0-24 hr) bile. The data indicated that a substantial amount of MK-499 was abso rbed by rats and dogs. MK-499, metabolite I (formed by loss of N-subst itution), and metabolite II (an acid formed by metabolic scission acro ss the benzopyran ring) each represented 30% of rat urinary label. Rat bile contained MK-499 (10%), II (20%), and IV (10%), which was formed by carbon-4 hydroxylation of the tetralin ring. Additionally, rat bil e included glutathione (V) and N-acetyl-1-cysteine (VI) conjugates of a ring-opened metabolite. Metabolite III, a positional isomer of IV, w as excreted in rat urine. The major labeled species excreted in dog bi le were unchanged MK-499 and its glucuronide (VII), which, respectivel y, represented 50% and 30% of the biliary radioactivity, MK-499 and a small amount of I represented dog urinary radioactivity. The bioavaila bility of MK-499 was high in dogs (100%) but low in rats (17%), This d ifference was probably due to the more extensive presystemic metabolis m of MK-499 in rats.