Received for publication March 2, 2009.
Revised May 18, 2009.
Accepted for publication June 9, 2009.

Involvement of Human Organic Cation Transporter 1 (OCT1) in the Hepatic Uptake of YM155 Monobromide, 1-(2-Methoxyethyl)-2-methyl-4,9-dioxo-3-(pyrazin-2-ylmethyl)-4,9-dihydro-1H-naphtho[2,3-d]imidazolium Bromide, a Novel, Small Molecule Survivin Suppressant

Abstract

YM155 monobromide, 1-(2-methoxyethyl)-2-methyl-4,9-dioxo-3-(pyrazin-2-ylmethyl)-4,9- dihydro-1H-naphtho[2,3-d]imidazolium bromide, which is a hydrophilic and cationic compound, exhibits anti-tumor activity in experimental human hormone refractory prostate carcinoma models. Urinary excretion was 18.3% to 28.6% of the dose in the clinical phase I study, and non-renal elimination may be explained by the biliary excretion of YM155 in its unchanged form. As the penetration through the sinusoidal membrane of the hepatocytes is the first step and an important part of biliary excretion, we evaluated the uptake of [¹⁴C]YM155 into human cryopreserved hepatocytes. YM155 was taken up into hepatocytes in a temperature- and concentration-dependent manner. The saturable uptake component was much higher than the non-saturable passive diffusion component. In vitro hepatic uptake clearance was consistent with the in vivo hepatic intrinsic clearance calculated using clinical study data. Hepatic uptake of YM155 was inhibited by organic cation transporter (OCT) inhibitors, and the half-maximal inhibitory concentration (IC₅₀) values for YM155 uptake were comparable to those reported for human OCT1-mediated transport. The interaction of YM155 with candidate transporter, OCT1, was also characterized using S2 cells stably expressing human OCT1 (OCT1-S2) cells. In OCT1-expressing S2 cells, YM155 inhibited the OCT1-mediated uptake of a typical OCT1 substrate, [¹⁴C]tetraethylammonium. In addition, YM155 was taken up into OCT1-S2 cells These results indicated that OCT1 was the predominant transporter for the hepatic uptake of YM155, and the transporter-mediated uptake clearance observed in vitro may account for the in vivo intrinsic hepatic clearance.

Key words: hepatic elimination, hepatic transport, hepatic uptake, hepatobiliary disposition, hepatobiliary transport, hepatocytes, in vitro-in vivo scaling, membrane transport, organic cation transport, transporters