title: Metabolism of MK-499, a class III antiarrhythmic agent, in rats and dogs.
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.
authors.affiliation: Drug Metabolism, Merck Research Laboratories, West Point, PA 19486, USA.
authors.forename: S
authors.initials: S
authors.lastname: Vickers
authors.forename: C A
authors.initials: CA
authors.lastname: Duncan
authors.forename: D E
authors.initials: DE
authors.lastname: Slaughter
authors.forename: B H
authors.initials: BH
authors.lastname: Arison
authors.forename: T
authors.initials: T
authors.lastname: Greber
authors.forename: T V
authors.initials: TV
authors.lastname: Olah
authors.forename: K P
authors.initials: KP
authors.lastname: Vyas
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001578:Benzopyrans / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008657:Metabolic Clearance Rate; D010880:Piperidines / Q000493:pharmacokinetics* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D017180:Tachycardia, Ventricular / Q000188:drug therapy / Q000378:metabolism*; D014018:Tissue Distribution
chemical_list: D000889:Anti-Arrhythmia Agents; D001578:Benzopyrans; D010880:Piperidines; C087257:L 706000