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First published on May 13, 2009; DOI: 10.1124/dmd.108.026294

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Received for publication December 22, 2008.
Revised May 11, 2009.
Accepted for publication May 11, 2009.

Identification of human metabolites of YM758, a novel If channel inhibitor, and investigation of the transporter-mediated renal and hepatic excretion of these metabolites

Ken-ichi Umehara 1*, Nobuaki Shirai 2, Takafumi Iwatsubo 1, Kiyoshi Noguchi 1, Takashi Usui 1, Hidetaka Kamimura 1

1 Astellas Pharma Inc. 2 Nemoto Science Co., Ltd.

* Address correspondence to: E-mail: kenichi.umehara{at}jp.astellas.com

Abstract

YM758 is a novel inhibitor of If channel ('funny' If current channel) which is expressed in the sinus node of heart, and being developed as a treatment for stable angina and atrial fibrillation. Its metabolites were identified in human urine, plasma, and feces by radio-HPLC and LC-MS/MS analyses after oral administration of [14C]-YM758. YM-252124, YM-385459, AS2036329, and the unchanged drug were detected as major constituents both in the urine and plasma, while YM-385461 was detected in the plasma, but not in the urine. The renal and hepatic uptake transporters for these metabolites were investigated by assessing their inhibitory effect on uptake activity in hOCT1-3/rOct1-3, hOAT1/rOat1, hOAT3/rOat3, OATP1B1/1B3-expressing HEK293 cells. IC50 values of YM-252124 on MPP 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 PAH, 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.


Key words: active transport, drug transport, hepatic transport, human pharmacokinetics, in vitro-in vivo prediction, inhibition, organic anion transport, organic cation transport, renal transport


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K.-i. Umehara, N. Nakada, K. Noguchi, T. Iwatsubo, T. Usui, and H. Kamimura
Investigation of Long-Term Retention of Unchanged (-)-N-{2-[(R)-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
Drug Metab. Dispos., November 1, 2009; 37(11): 2137 - 2144.
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