Abstract
1-(2-Methoxyethyl)-2-methyl-4,9-dioxo-3-(pyrazin-2-ylmethyl)-4,9-dihydro-1H-naphtho[2,3-d]imidazolium bromide (YM155 monobromide) is a novel small-molecule survivin suppressant that induces the down-regulation of survivin and exhibits potent antitumor activity in nude mice bearing human hormone refractory prostate carcinoma cell line PC-3. Although YM155, which has a cationic moiety in its structure, is influxed into its pharmacologically effective site (cancer cells) and one of its eliminating organs (hepatocytes) in a transporter-mediated manner, the mechanism seems to be different between the two cell types. The other eliminating organ is the kidney. In this study, the transport of [14C]YM155 was characterized by using human embryonic kidney 293 cells expressing organic cation transporter 1 (OCT1/SLC22A1), OCT2 (SLC22A2), and OCT3 (SLC22A3). YM155 inhibited the uptake of a typical substrate [3H]1-methyl-4-phenylpyridinium via OCT1, OCT2, and OCT3 with IC50 values of 23.8, 15.9, and 108 μM, respectively. The time- and saturable concentration-dependent uptake of [14C]YM155 was observed in cells expressing OCT1 and OCT2 with Km values of 22.1 and 2.67 μM, respectively, but not in cells expressing OCT3. By taking into consideration the tissue distribution and localization of each transporter, these results suggest that, in humans, YM155 is taken up from the blood into hepatocytes and proximal tubular cells via OCT1 and OCT2, respectively. The comparison of the IC50 values of OCT inhibitors and Km values for the uptake of YM155 into cells expressing OCTs with those into cancer cell lines indicated that transporter(s) other than OCT1 and OCT2 are involved in the uptake of YM155 into cancer cell lines.
Footnotes
Parts of this work were previously presented in abstract form follows: Minematsu T, Iwai M, Umehara K, Usui T, and Kamimura H (2007) Human organic cation transporter 1-mediated transport of YM155, a novel survivin suppressant. 8th International ISSX Meeting 2007; 2007 Oct 9–12; Sendai, Japan. Drug Metab Rev 39 (Suppl 1):67; Iwai M, Minematsu T, Umehara K, Usui T, and Kamimura H (2008) Role of organic cation transporter 1 (OCT1), OCT2, and OCT3 in the pharmacokinetics of YM155, a novel survivin suppressant. 15th North American ISSX Meeting 2008; 2008 Oct 12–16; San Diego, CA. Drug Metab Rev 40 (Suppl 3):273.
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.109.028142
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- YM155 monobromide
- 1-(2-methoxyethyl)-2-methyl-4,9-dioxo-3-(pyrazin-2-ylmethyl)-4,9-dihydro-1H-naphtho[2,3-d]imidazolium bromide
- OCT
- organic cation transporter
- hOCT-S2
- human OCT-expressing mouse kidney-derived S2 cells
- HEK
- human embryonic kidney
- hOCT-HEK
- human OCT-expressing HEK293 cells
- MPP
- 1-methyl-4-phenylpyridinium
- [S]
- substrate concentration
- V
- uptake velocity
- OCTN
- novel organic cation transporter
- OAT
- organic anion transporter
- OATP
- organic anion transporter polypeptide.
- Received June 10, 2009.
- Accepted October 9, 2009.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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