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 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.
- YM758, (−)-N-{2-[(R)-3-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidino]ethyl}-4-fluorobenzamide
- If channel, “funny” If current channel
- YM-385462, 4-fluoro-N-(2-{(3R)-3-[(4-hydroxy-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl]piperidin-1-yl}ethyl)benzamide
- YM-385463, 4-fluoro-N-(2-{(3R)-3-[(4-hydroxy-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl]piperidin-1-yl}ethyl)benzamide
- YM-385459, (5R)-5-[(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl]piperidin-2-one
- YM-252124, 6,7-dimethoxy-2-[(3R)-piperidin-3-ylcarbonyl]-1,2,3,4-tetrahydroisoquinoline
- YM-385461, N-(4-fluorobenzoyl)glycine
- YM-234903, (3R)-1-{2-[(4-fluorobenzoyl)amino]ethyl} piperidine-3-carboxylic acid
- YM-396944, 2-[2-({[(3R)-1-{2-[(4-fluorobenzoyl)amino]ethyl}piperidin-3-yl]carbonyl}amino)ethyl]-4,5-dimethoxybenzoic acid
- YM-394111, 4-fluoro-N-(2-{(3R)-3-[(6-hydroxy-7-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl]piperidin-1-yl}ethyl)benzamide
- YM-394112, 4-fluoro-N-(2-{(3R)-3-[(7-hydroxy-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl]piperidin-1-yl}ethyl)benzamide
- HPLC, high-performance liquid chromatography
- LC, liquid chromatography
- MS, mass spectrometry
- Tmax, time to reach the maximum concentration.
Footnotes
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.109.027813
- Received December 19, 2008.
- Accepted May 15, 2009.
- Copyright © 2009 by The American Society for Pharmacology and Experimental Therapeutics
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