title: Investigation of long-term retention of unchanged (-)-N-{2-[(R)-3-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidino]ethyl}-4-fluorobenzamide, a novel "funny" If current channel inhibitor, and its metabolites in the eyeball and thoracic aorta of rats.
abstract: (-)-N-{2-[(R)-3-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidino]ethyl}-4-fluorobenzamide (YM758), a novel "funny" If current channel inhibitor, was being developed as a treatment for stable angina and atrial fibrillation. After a single oral administration of (14)C-YM758, extensive accumulation and long-term retention of radioactivity were observed in the eyeballs of nonalbino rats and in the thoracic aorta of albino/nonalbino rats. Radioluminograms of the eyeballs of nonalbino rats indicated that the radioactivity was localized to the uveal tract, which suggests that the radioactivity may be positively charged and bound mainly to the melanins. Treatment with a mixture of 2 mol/l hydrochloric acid and methanol (5:95, v/v) allowed for the recovery of the major portion of radioactivity from the eyeball, which suggests reversible binding. The radioactive constituents in eyeballs consisted of the unchanged drug (YM758) and three metabolites [mainly 6,7-dimethoxy-2-[(3R)-piperidin-3-ylcarbonyl]-1,2,3,4-tetrahydroisoquinoline (YM-252124)]. Using the organic solvent mixture described above, almost all of the radioactivity was not collected from the thoracic aorta, and approximately 90% was recovered by treatment with elastase, which suggests that some metabolites covalently bind to the elastin fiber localized in the tunica media.
authors.affiliation: Drug Metabolism Research Laboratories, Drug Discovery Research, Astellas Pharma Inc., 1-8, Azusawa 1-chome, Itabashi-ku, Tokyo 174-8511, Japan. umeken0727@gmail.com
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Umehara
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Nakada
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Noguchi
authors.forename: Takafumi
authors.initials: T
authors.lastname: Iwatsubo
authors.forename: Takashi
authors.initials: T
authors.lastname: Usui
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Kamimura
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism*; D001549:Benzamides / Q000378:metabolism* / Q000494:pharmacology; D005123:Eye / Q000187:drug effects / Q000378:metabolism*; D007546:Isoquinolines / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D011506:Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014018:Tissue Distribution / Q000187:drug effects / Q000502:physiology; D000097795:ATPase Inhibitory Protein
chemical_list: D001549:Benzamides; D007546:Isoquinolines; D011506:Proteins; D000097795:ATPase Inhibitory Protein; C530155:YM 758