TY - JOUR T1 - Investigation of Long-Term Retention of Unchanged (−)-<em>N</em>-{2-[(<em>R</em>)-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 JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 2137 LP - 2144 DO - 10.1124/dmd.109.027813 VL - 37 IS - 11 AU - Ken-ichi Umehara AU - Naoyuki Nakada AU - Kiyoshi Noguchi AU - Takafumi Iwatsubo AU - Takashi Usui AU - Hidetaka Kamimura Y1 - 2009/11/01 UR - http://dmd.aspetjournals.org/content/37/11/2137.abstract N2 - (−)-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 14C-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. Copyright © 2009 by The American Society for Pharmacology and Experimental Therapeutics ER -