Received for publication January 31, 2008.
Revised March 3, 2008.
Accepted for publication March 5, 2008.

Hepatic uptake and excretion of YM758, a novel If channel inhibitor, in rats and humans

Abstract

YM758, a novel If channel inhibitor, is being developed as a treatment for stable angina and atrial fibrillation. The hepatic uptake/excretion of YM758 was clarified using transporter-expressing mammalian cells and hepatocytes mainly in humans and partly in rats. cDNA-expressing HEK293 cells were used to determine that YM758 was greatly taken up via OATP1B1 and slightly via hOCT1/rOct1, but not via OATP1B3. In addition, the uptake of E₂17G via OATP1B1 was inhibited in the presence of YM758, whereas that via OATP1B3 was not. In contrast, time-dependent uptake of YM758 into rat/human hepatocytes at 37 °C was observed, as was concentration-dependent uptake into human hepatocytes (K_m value of 87.9 µmol/l). This saturable uptake of YM758 into human hepatocytes was inhibited in the presence of quinidine (an inhibitor for OATP1B1), but not cimetidine (an inhibitor for hOCT family). Moreover, the permeation clearance ratios for the transcellular transport of YM758 across MDR1-expressing LLC-PK1 cells were extensively higher than those across LLC-PK1 cells, which indicates that MDR1-mediated transport is one of the possible pathways through which YM758 may be excreted into the bile. These results indicate that YM758 is taken up into hepatocytes mainly via OATP1B1, but not via hOCT1, and is excreted into the bile via MDR1 in humans; however, passive diffusion or an unknown uptake/excretion mechanism could be at work in the hepatocytes. This study is the first to clarify the saturable hepatic uptake and/or the excretion mechanism by the If channel inhibitor.

Key words: active transport, drug development, hepatobiliary transport

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