Vol. 26, Issue 5, 388-395, May 1998

Metabolism of MK-499, a Class III Antiarrhythmic Agent, in Rats and Dogs

Stanley Vickers, Carol A. Duncan, Donald E. Slaughter, Byron H. Arison, Terrence Greber, Timothy V. Olah, and Kamlesh P. Vyas

Drug Metabolism, Merck Research Laboratories

MK-499 [(+)-N-[1'-(6-cyano-1, 2, 3, 4-tetrahydro-2(R)-naphthalenyl)-3,4-dihydro-4(R)-hydroxyspiro(2H-1-benzopyran-2,4'-piperidin)-6-yl]methanesulfonamide] monohydrochloride is an investigational class III antiarrhythmic agent for treatment of malignant ventricular tachyarrhythmias. The disposition of [³H]MK-499 and [¹⁴C]MK-499 was studied in rats and dogs after oral and iv administration. MK-499 was concentrated in organs of excretion and the heart. In the rat, urinary radioactivity elimination values after iv (0.5 mg/kg) and oral (6.25 mg/kg) doses were 21 ± 3% and 10 ± 2%, respectively. Corresponding fecal recoveries were 68 ± 6% and 78 ± 7%. Similar results were found after corresponding doses of [¹⁴C]MK-499. In dogs, urine and feces accounted for 16 ± 3% and 75 ± 4% of recovered radioactivity after a [³H]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 accounted for 39 ± 5% and 41 ± 18% of [³H] and [¹⁴C] oral doses in rats, respectively. Dogs excreted 34% of [³H] oral dose in (0-24 hr) bile. The data indicated that a substantial amount of MK-499 was absorbed by rats and dogs. MK-499, metabolite I (formed by loss of N-substitution), and metabolite II (an acid formed by metabolic scission across 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 bile included glutathione (V) and N-acetyl-1-cysteine (VI) conjugates of a ring-opened metabolite. Metabolite III, a positional isomer of IV, was excreted in rat urine. The major labeled species excreted in dog bile were unchanged MK-499 and its glucuronide (VII), which, respectively, represented 50% and 30% of the biliary radioactivity. MK-499 and a small amount of I represented dog urinary radioactivity. The bioavailability of MK-499 was high in dogs (100%) but low in rats (17%). This difference was probably due to the more extensive presystemic metabolism of MK-499 in rats.