Abstract
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.
Footnotes
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Send reprint requests to: Stanley Vickers, Ph.D., WP26A-2044, Drug Metabolism, Merck Research Laboratories, West Point, PA 19486.
- Abbreviations used are::
- HPLC
- high pressure liquid chromatography
- AUC
- area under the curve
- Received August 27, 1997.
- Accepted January 16, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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