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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.
- Source :
-
Drug metabolism and disposition: the biological fate of chemicals [Drug Metab Dispos] 2009 Aug; Vol. 37 (8), pp. 1646-57. Date of Electronic Publication: 2009 May 13. - Publication Year :
- 2009
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Abstract
- (-)-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.
- Subjects :
- Administration, Oral
Adult
Benzamides administration & dosage
Benzamides blood
Benzamides urine
Biological Transport
Biotransformation
Carbon Radioisotopes
Cardiovascular Agents administration & dosage
Cardiovascular Agents blood
Cardiovascular Agents urine
Catecholamine Plasma Membrane Transport Proteins metabolism
Cell Line
Chromatography, High Pressure Liquid
Feces chemistry
Humans
Isoquinolines administration & dosage
Isoquinolines blood
Isoquinolines urine
Kidney drug effects
Liver drug effects
Male
Membrane Transport Modulators administration & dosage
Membrane Transport Modulators blood
Membrane Transport Modulators urine
Metabolomics methods
Middle Aged
Organic Anion Transport Protein 1 metabolism
Organic Anion Transporters, Sodium-Independent metabolism
Organic Cation Transport Proteins metabolism
Organic Cation Transporter 1 antagonists & inhibitors
Organic Cation Transporter 1 genetics
Organic Cation Transporter 2
Species Specificity
Tandem Mass Spectrometry
Transfection
Young Adult
Benzamides pharmacokinetics
Cardiovascular Agents pharmacokinetics
Isoquinolines pharmacokinetics
Kidney metabolism
Liver metabolism
Membrane Transport Modulators pharmacokinetics
Organic Cation Transporter 1 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1521-009X
- Volume :
- 37
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Drug metabolism and disposition: the biological fate of chemicals
- Publication Type :
- Academic Journal
- Accession number :
- 19439489
- Full Text :
- https://doi.org/10.1124/dmd.108.026294