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Research ArticleArticle

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

Ken-ichi Umehara, Nobuaki Shirai, Takafumi Iwatsubo, Kiyoshi Noguchi, Takashi Usui and Hidetaka Kamimura
Drug Metabolism and Disposition August 2009, 37 (8) 1646-1657; DOI: https://doi.org/10.1124/dmd.108.026294
Ken-ichi Umehara
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Nobuaki Shirai
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Takafumi Iwatsubo
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Kiyoshi Noguchi
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Takashi Usui
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Hidetaka Kamimura
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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 chromatographytandem mass spectrometry analyses after oral administration of [14C]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 β-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. IC50 values of YM-252124 for 1-methyl-4-phenylpyridinium uptake via hOCT2 and rOct2 were 93.9 and 1700 μM, 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.

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  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.108.026294.

  • ABBREVIATIONS: If channel, “funny” If current channel; YM758, (–)-N-{2-[(R)-3-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidino]ethyl}-4-fluorobenzamide; h, human; r, rat; OCT/Oct, organic cation transporter; MDR1/Mdr1, multidrug resistance 1; OAT/rOat, organic anion transporter; MRP/Mrp, multidrug resistance-associated protein; OATP1B1, organic anion transporting polypeptide 1B1/-C/2; OATP1B3, organic anion transporting polypeptide 1B3/8; HPLC, high-performance liquid chromatography; LC, liquid chromatography; MS/MS, tandem mass spectrometry; MPP, 1-methyl-4-phenylpyridinium; PAH, p-aminohippuric acid; ES, estrone-3-sulfate; E217βG, estradiol-d-17β-glucuronide; AUC, area under the curve; CLsec, secretion clearance; CLr, renal clearance; YM-252124, 6,7-dimethoxy-2-[(3R)-piperidin-3-ylcarbonyl]-1,2,3,4-tetrahydroisoquinoline; YM-385459, (5R)-5-[(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl]piperidin-2-one; YM-385461, N-(4-fluorobenzoyl)glycine; AS2036329, 2-{[(3R)-1-{2-[(4-fluorobenzoyl)amino]ethyl}piperidin-3-yl]carbonyl}-7-methoxy-1,2,3,4-tetrahydoisoquinolin-6-yl β-d-glucopyranosiduronic acid.

    • Accepted May 11, 2009.
    • Received December 19, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 37 (8)
Drug Metabolism and Disposition
Vol. 37, Issue 8
1 Aug 2009
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Research ArticleArticle

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

Ken-ichi Umehara, Nobuaki Shirai, Takafumi Iwatsubo, Kiyoshi Noguchi, Takashi Usui and Hidetaka Kamimura
Drug Metabolism and Disposition August 1, 2009, 37 (8) 1646-1657; DOI: https://doi.org/10.1124/dmd.108.026294

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Research ArticleArticle

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

Ken-ichi Umehara, Nobuaki Shirai, Takafumi Iwatsubo, Kiyoshi Noguchi, Takashi Usui and Hidetaka Kamimura
Drug Metabolism and Disposition August 1, 2009, 37 (8) 1646-1657; DOI: https://doi.org/10.1124/dmd.108.026294
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