Identification of Human Metabolites of (–)-N-{2-[(R)-3-(6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidino]ethyl}-4-fluorobenzamide (YM758), a Novel If Channel Inhibitor, and Investigation of the Transporter-Mediated Renal and Hepatic Excretion of These Metabolites
| العنوان: | Identification of Human Metabolites of (–)-N-{2-[(R)-3-(6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidino]ethyl}-4-fluorobenzamide (YM758), a Novel If Channel Inhibitor, and Investigation of the Transporter-Mediated Renal and Hepatic Excretion of These Metabolites |
|---|---|
| المؤلفون: | K.-I. Umehara, Nobuaki Shirai, Hidetaka Kamimura, Kiyoshi Noguchi, Takafumi Iwatsubo, Takashi Usui |
| المصدر: | Drug Metabolism and Disposition. 37:1646-1657 |
| بيانات النشر: | American Society for Pharmacology & Experimental Therapeutics (ASPET), 2009. |
| سنة النشر: | 2009 |
| مصطلحات موضوعية: | Adult, Male, Organic Cation Transport Proteins, Organic anion transporter 1, Stereochemistry, Metabolite, Administration, Oral, Pharmaceutical Science, Organic Anion Transporters, Sodium-Independent, Kidney, Transfection, Cell Line, Excretion, Feces, Young Adult, chemistry.chemical_compound, Organic Anion Transport Protein 1, Species Specificity, Tandem Mass Spectrometry, Membrane Transport Modulators, medicine, Humans, Metabolomics, Carbon Radioisotopes, Biotransformation, Chromatography, High Pressure Liquid, Pharmacology, Chromatography, Organic cation transport proteins, biology, Tetrahydroisoquinoline, Organic Cation Transporter 1, Organic Cation Transporter 2, Kidney metabolism, Biological Transport, Cardiovascular Agents, Middle Aged, Isoquinolines, medicine.anatomical_structure, Liver, chemistry, Renal physiology, Benzamides, biology.protein, Catecholamine Plasma Membrane Transport Proteins |
| الوصف: | (-)-N-{2-[(R)-3-(6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidino]ethyl}-4-fluorobenzamide (YM758) is a novel inhibitor of the "funny" If current channel (If channel) that is expressed in the sinus node of heart and is being developed as a treatment for stable angina and atrial fibrillation. Its metabolites were identified in human urine, plasma, and feces by radio-high-performance liquid chromatography and liquid chromatography-tandem mass spectrometry analyses after oral administration of [(14)C]YM758. 6,7-Dimethoxy-2-[(3R)-piperidin-3-ylcarbonyl]-1,2,3,4-tetrahydroisoquinoline (YM-252124), (5R)-5-[(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl]piperidin-2-one (YM-385459), 2-{[(3R)-1-{2-[(4-fluorobenzoyl)amino]ethyl}piperidin-3-yl]carbonyl}-7-methoxy-1,2,3,4-tetrahydroisonolin-6-yl beta-D-glucopyranosiduronic acid (AS2036329), and the unchanged drug were detected as major constituents in both urine and plasma, whereas N-(4-fluorobenzoyl)glycine (YM-385461) was detected in plasma, but not in urine. The renal and hepatic uptake transporters for these metabolites were investigated by assessing their inhibitory effect on uptake activity in human (h) organic cation transporter (OCT) 1-3/rat (r) Oct1-3, human organic anion transporter (OAT) 1/rOat1, hOAT3/rOat3, and organic anion-transporting protein 1B1/1B3-expressing HEK293 cells. IC(50) values of YM-252124 for 1-methyl-4-phenylpyridinium uptake via hOCT2 and rOct2 were 93.9 and 1700 microM, respectively, suggesting that this metabolite is secreted into urine via hOCT2/rOct2 and that the large difference in the inhibitory potentials between hOCT2 and rOct2 explains the species difference in the urinary excretion ratio of the radioactivity. The renal secretion of YM-385461, one derivative of p-aminohippuric acid, via hOAT1/rOat1, and hepatic uptake of YM-252124 via hOCT1/rOct1 was also expected. This kind of study was useful in investigating the relationship between the urinary/hepatic elimination and the transport activity for metabolites. |
| تدمد: | 1521-009X 0090-9556 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6946fb150b03b68451199281388ba1fbTest https://doi.org/10.1124/dmd.108.026294Test |
| رقم الانضمام: | edsair.doi.dedup.....6946fb150b03b68451199281388ba1fb |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 1521009X 00909556 |
|---|