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Hidetaka Kamimura - One of the best experts on this subject based on the ideXlab platform.
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characterization of human organic cation transporter 1 oct1 slc22a1 and oct2 slc22a2 mediated transport of 1 2 methoxyethyl 2 methyl 4 9 dioxo 3 pyrazin 2 ylmethyl 4 9 dihydro 1h naphtho 2 3 d imidazolium bromide ym155 monobromide a novel small molec
Drug Metabolism and Disposition, 2010Co-Authors: Tsuyoshi Minematsu, Megumi Iwai, Takashi Usui, Kenichi Umehara, Hidetaka KamimuraAbstract:1-(2-Methoxyethyl)-2-methyl-4,9-dioxo-3-(pyrazin-2-ylmethyl)-4,9-dihydro-1 H -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 [ 14 C]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 [ 3 H]1-methyl-4-phenylpyridinium via OCT1, OCT2, and OCT3 with IC 50 values of 23.8, 15.9, and 108 μM, respectively. The time- and saturable concentration-dependent uptake of [ 14 C]YM155 was observed in cells expressing OCT1 and OCT2 with K m 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 IC 50 values of OCT inhibitors and K m 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.
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carrier mediated uptake of 1 2 methoxyethyl 2 methyl 4 9 dioxo 3 pyrazin 2 ylmethyl 4 9 dihydro 1h naphtho 2 3 d imidazolium bromide ym155 monobromide a novel small molecule survivin suppressant into human solid tumor and lymphoma cells
Drug Metabolism and Disposition, 2009Co-Authors: Tsuyoshi Minematsu, Megumi Iwai, Kenji Sugimoto, Nobuaki Shirai, Takahito Nakahara, Takashi Usui, Hidetaka KamimuraAbstract: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 the human hormone refractory prostate carcinoma cell line PC-3. In this study, radioluminographic determination of the in vivo distribution of radioactivity after administration of [14C]YM155 to PC-3-xenografted nude mice revealed a relatively high level of radioactivity in the PC-3 xenograft. Therefore, the uptake of [14C]YM155 was further characterized in vitro using PC-3, lung cancer (Calu-6 and NCI-H358), malignant melanoma (A375 and SK-MEL-5), and non-Hodgkin9s lymphoma (RL and Ramos) cell lines. The uptake of [14C]YM155 in these cell lines was dependent on incubation time, temperature, and drug concentration. The Michaelis-Menten constant values were similar among the seven cell lines (0.189–0.367 μM). The effects of various compounds on the uptake of [14C]YM155 were tested in PC-3, Calu-6, A375, RL, and Ramos cell lines. Of the compounds tested, the cationic transporter substrates/inhibitors (tetraethylammonium, 1-methyl-4-phenylpyridium, cimetidine, prazosin, corticosterone, verapamil, amantadine, procainamide, and N-methylnicotinamide) inhibited the uptake of [14C]YM155 to a similar extent among the five cell lines. The half-maximal inhibitory concentration values (IC50) of several compounds for the uptake of [14C]YM155 into PC-3 differed from those reported in the literature for human organic cation transporter 1 (OCT1/SLC22A1), OCT2 (SLC22A2), and OCT3 (SLC22A3). To summarize, YM155 was taken up into cancer cells in a carrier-mediated manner and with a similar affinity among all the cancer cell lines tested. An influx transporter(s) may contribute to this process.
Tsuyoshi Minematsu - One of the best experts on this subject based on the ideXlab platform.
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characterization of human organic cation transporter 1 oct1 slc22a1 and oct2 slc22a2 mediated transport of 1 2 methoxyethyl 2 methyl 4 9 dioxo 3 pyrazin 2 ylmethyl 4 9 dihydro 1h naphtho 2 3 d imidazolium bromide ym155 monobromide a novel small molec
Drug Metabolism and Disposition, 2010Co-Authors: Tsuyoshi Minematsu, Megumi Iwai, Takashi Usui, Kenichi Umehara, Hidetaka KamimuraAbstract:1-(2-Methoxyethyl)-2-methyl-4,9-dioxo-3-(pyrazin-2-ylmethyl)-4,9-dihydro-1 H -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 [ 14 C]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 [ 3 H]1-methyl-4-phenylpyridinium via OCT1, OCT2, and OCT3 with IC 50 values of 23.8, 15.9, and 108 μM, respectively. The time- and saturable concentration-dependent uptake of [ 14 C]YM155 was observed in cells expressing OCT1 and OCT2 with K m 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 IC 50 values of OCT inhibitors and K m 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.
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carrier mediated uptake of 1 2 methoxyethyl 2 methyl 4 9 dioxo 3 pyrazin 2 ylmethyl 4 9 dihydro 1h naphtho 2 3 d imidazolium bromide ym155 monobromide a novel small molecule survivin suppressant into human solid tumor and lymphoma cells
Drug Metabolism and Disposition, 2009Co-Authors: Tsuyoshi Minematsu, Megumi Iwai, Kenji Sugimoto, Nobuaki Shirai, Takahito Nakahara, Takashi Usui, Hidetaka KamimuraAbstract: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 the human hormone refractory prostate carcinoma cell line PC-3. In this study, radioluminographic determination of the in vivo distribution of radioactivity after administration of [14C]YM155 to PC-3-xenografted nude mice revealed a relatively high level of radioactivity in the PC-3 xenograft. Therefore, the uptake of [14C]YM155 was further characterized in vitro using PC-3, lung cancer (Calu-6 and NCI-H358), malignant melanoma (A375 and SK-MEL-5), and non-Hodgkin9s lymphoma (RL and Ramos) cell lines. The uptake of [14C]YM155 in these cell lines was dependent on incubation time, temperature, and drug concentration. The Michaelis-Menten constant values were similar among the seven cell lines (0.189–0.367 μM). The effects of various compounds on the uptake of [14C]YM155 were tested in PC-3, Calu-6, A375, RL, and Ramos cell lines. Of the compounds tested, the cationic transporter substrates/inhibitors (tetraethylammonium, 1-methyl-4-phenylpyridium, cimetidine, prazosin, corticosterone, verapamil, amantadine, procainamide, and N-methylnicotinamide) inhibited the uptake of [14C]YM155 to a similar extent among the five cell lines. The half-maximal inhibitory concentration values (IC50) of several compounds for the uptake of [14C]YM155 into PC-3 differed from those reported in the literature for human organic cation transporter 1 (OCT1/SLC22A1), OCT2 (SLC22A2), and OCT3 (SLC22A3). To summarize, YM155 was taken up into cancer cells in a carrier-mediated manner and with a similar affinity among all the cancer cell lines tested. An influx transporter(s) may contribute to this process.
Hermann Koepsell - One of the best experts on this subject based on the ideXlab platform.
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Inhibition of oat3-mediated renal uptake as a mechanism for drug-drug interaction between fexofenadine and probenecid. Drug metabolism and disposition: the biological fate of chemicals 2006;34:743–7. [PubMed: 16455804
2016Co-Authors: Harunobu Tahara, Hermann Koepsell, Kazuya Maeda, Eiichi Fuse, Hiroyuki Kusuhara, Yuichi SugiyamaAbstract:Fexofenadine, a nonsedating antihistamine drug, is effective for the treatment of seasonal allergic rhinitis and chronic urticaria. Simultaneous administration of probenecid increases the plasma concentration of fexofenadine due to an inhibition of its renal elimination in healthy volunteers (Clin Pharmacol Ther 77:17–23, 2005). The purpose of the present study is to investigate the pos-sibility that the drug-drug interaction between fexofenadine and probenecid involves the renal basolateral uptake process. The uptake of fexofenadine was determined in HEK293 cells express-ing human organic anion transporter 1 (OAT1/SLC22A6), OAT2 (SLC22A7), OAT3 (SLC22A8), and organic cation transporter 2 (OCT2/SLC22A2). Only hOAT3-HEK showed a significantly greater accumulation of fexofenadine than that in vector-HEK, which was saturable with Km and Vmax values of 70.2 M and 120 pmol/ min/mg protein, respectively. Inhibition potency of probenecid fo
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DNA methylation is associated with downregulation of the organic cation transporter OCT1 (SLC22A1) in human hepatocellular carcinoma.
Genome medicine, 2011Co-Authors: Elke Schaeffeler, Hermann Koepsell, Ulrich M Zanger, Claus Hellerbrand, Anne T Nies, Stefan Winter, Stephan Kruck, Ute Hofmann, Heiko Van Der Kuip, Matthias SchwabAbstract:Background Organic cation transporters (OCTs) determine not only physiological processes but are also involved in the cellular uptake of anticancer agents. Based on microarray analyses in hepatocellular carcinoma (HCC), SLC22A1/OCT1 mRNA seems to be downregulated, but systematic protein expression data are currently missing. Moreover, the underlying molecular mechanisms responsible for altered SLC22A1 expression in HCC are not fully understood. Therefore, we investigated the role of DNA methylation in the transcriptional regulation of the family members SLC22A1/OCT1, SLC22A2/OCT2 and SLC22A3/OCT3 in HCC.
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organic cation transporters octs mates in vitro and in vivo evidence for the importance in drug therapy
Handbook of experimental pharmacology, 2011Co-Authors: Anne T Nies, Hermann Koepsell, Katja Damme, Matthias SchwabAbstract:Organic cation transporters (OCTs) of the solute carrier family (SLC) 22 and multidrug and toxin extrusion (MATE) transporters of the SLC47 family have been identified as uptake and efflux transporters, respectively, for xenobiotics including several clinically used drugs such as the antidiabetic agent metformin, the antiviral agent lamivudine, and the anticancer drug oxaliplatin. Expression of human OCT1 (SLC22A1) and OCT2 (SLC22A2) is highly restricted to the liver and kidney, respectively. By contrast, OCT3 (SLC22A3) is more widely distributed. MATEs (SLC47A1, SLC47A2) are predominantly expressed in human kidney. Data on in vitro studies reporting a large number of substrates and inhibitors of OCTs and MATEs are systematically summarized. Several genetic variants of human OCTs and in part of MATE1 have been reported, and some of them result in reduced in vitro transport activity corroborating data from studies with knockout mice. A comprehensive overview is given on currently known genotype–phenotype correlations for variants in OCTs and MATE1 related to protein expression, pharmacokinetics/-dynamics of transporter substrates, treatment outcome, and disease susceptibility.
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expression of organic cation transporters oct1 slc22a1 and oct3 SLC22A3 is affected by genetic factors and cholestasis in human liver
Hepatology, 2009Co-Authors: Anne T Nies, Hermann Koepsell, Ulrich M Zanger, Stefan Winter, Oliver Burk, Kathrin Klein, Reinhold Kerb, Dietrich Keppler, Matthias SchwabAbstract:An important function of hepatocytes is the biotransformation and elimination of various drugs, many of which are organic cations and are taken up by organic cation transporters (OCTs) of the solute carrier family 22 (SLC22). Because interindividual variability of OCT expression may affect response to cationic drugs such as metformin, we systematically investigated genetic and nongenetic factors of OCT1/SLC22A1 and OCT3/SLC22A3 expression in human liver. OCT1 and OCT3 expression (messenger RNA [mRNA], protein) was analyzed in liver tissue samples from 150 Caucasian subjects. Hepatic OCTs were localized by way of immunofluorescence microscopy. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and genome-wide single-nucleotide polymorphism microarray technology served to genotype 92 variants in the SLC22A1-A3/OCT1-3 gene cluster. Transport of metformin by recombinant human OCT1 and OCT3 was compared using transfected cells. OCT1 mRNA and protein expression varied 113- and 83-fold, respectively; OCT3 mRNA expression varied 27-fold. OCT1 transcript levels were on average 15-fold higher compared with OCT3. We localized the OCT3 protein to the basolateral hepatocyte membrane and identified metformin as an OCT3 substrate. OCT1 and OCT3 expression are independent of age and sex but were significantly reduced in liver donors diagnosed as cholestatic (P ≤ 0.01). Several haplotypes for OCT1 and OCT3 were identified. Multivariate analysis adjusted for multiple testing showed that only the OCT1-Arg61Cys variant (rs12208357) strongly correlated with decreased OCT1 protein expression (P < 0.0001), and four variants in OCT3 (rs2292334, rs2048327, rs1810126, rs3088442) were associated with reduced OCT3 mRNA levels (P = 0.03). Conclusion: We identified cholestasis and genetic variants as critical determinants for considerable interindividual variability of hepatic OCT1 and OCT3 expression. This indicates consequences for hepatic elimination of and response to OCT substrates such as metformin. (HEPATOLOGY 2009.)
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Polyspecific Organic Cation Transporters: Structure, Function, Physiological Roles, and Biopharmaceutical Implications
Pharmaceutical Research, 2007Co-Authors: Hermann Koepsell, Katrin Lips, Christopher VolkAbstract:The body is equipped with broad-specificity transporters for the excretion and distribution of endogeneous organic cations and for the uptake, elimination and distribution of cationic drugs, toxins and environmental waste products. This group of transporters consists of the electrogenic cation transporters OCT1-3 ( SLC22A1-3 ), the cation and carnitine transporters OCTN1 ( SLC22A4 ), OCTN2 ( SLC22A5 ) and OCT6 ( SLC22A16 ), and the proton/cation antiporters MATE1, MATE2-K and MATE2-B. The transporters show broadly overlapping sites of expression in many tissues such as small intestine, liver, kidney, heart, skeletal muscle, placenta, lung, brain, cells of the immune system, and tumors. In epithelial cells they may be located in the basolateral or luminal membranes. Transcellular cation movement in small intestine, kidney and liver is mediated by the combined action of electrogenic OCT-type uptake systems and MATE-type efflux transporters that operate as cation/proton antiporters. Recent data showed that OCT-type transporters participate in the regulation of extracellular concentrations of neurotransmitters in brain, mediate the release of acetylcholine in non-neuronal cholinergic reactions, and are critically involved in the regulation of histamine release from basophils. The recent identification of polymorphisms in human OCTs and OCTNs allows the identification of patients with an increased risk for adverse drug reactions. Transport studies with expressed OCTs will help to optimize pharmacokinetics during development of new drugs.
Takashi Usui - One of the best experts on this subject based on the ideXlab platform.
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characterization of human organic cation transporter 1 oct1 slc22a1 and oct2 slc22a2 mediated transport of 1 2 methoxyethyl 2 methyl 4 9 dioxo 3 pyrazin 2 ylmethyl 4 9 dihydro 1h naphtho 2 3 d imidazolium bromide ym155 monobromide a novel small molec
Drug Metabolism and Disposition, 2010Co-Authors: Tsuyoshi Minematsu, Megumi Iwai, Takashi Usui, Kenichi Umehara, Hidetaka KamimuraAbstract:1-(2-Methoxyethyl)-2-methyl-4,9-dioxo-3-(pyrazin-2-ylmethyl)-4,9-dihydro-1 H -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 [ 14 C]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 [ 3 H]1-methyl-4-phenylpyridinium via OCT1, OCT2, and OCT3 with IC 50 values of 23.8, 15.9, and 108 μM, respectively. The time- and saturable concentration-dependent uptake of [ 14 C]YM155 was observed in cells expressing OCT1 and OCT2 with K m 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 IC 50 values of OCT inhibitors and K m 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.
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carrier mediated uptake of 1 2 methoxyethyl 2 methyl 4 9 dioxo 3 pyrazin 2 ylmethyl 4 9 dihydro 1h naphtho 2 3 d imidazolium bromide ym155 monobromide a novel small molecule survivin suppressant into human solid tumor and lymphoma cells
Drug Metabolism and Disposition, 2009Co-Authors: Tsuyoshi Minematsu, Megumi Iwai, Kenji Sugimoto, Nobuaki Shirai, Takahito Nakahara, Takashi Usui, Hidetaka KamimuraAbstract: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 the human hormone refractory prostate carcinoma cell line PC-3. In this study, radioluminographic determination of the in vivo distribution of radioactivity after administration of [14C]YM155 to PC-3-xenografted nude mice revealed a relatively high level of radioactivity in the PC-3 xenograft. Therefore, the uptake of [14C]YM155 was further characterized in vitro using PC-3, lung cancer (Calu-6 and NCI-H358), malignant melanoma (A375 and SK-MEL-5), and non-Hodgkin9s lymphoma (RL and Ramos) cell lines. The uptake of [14C]YM155 in these cell lines was dependent on incubation time, temperature, and drug concentration. The Michaelis-Menten constant values were similar among the seven cell lines (0.189–0.367 μM). The effects of various compounds on the uptake of [14C]YM155 were tested in PC-3, Calu-6, A375, RL, and Ramos cell lines. Of the compounds tested, the cationic transporter substrates/inhibitors (tetraethylammonium, 1-methyl-4-phenylpyridium, cimetidine, prazosin, corticosterone, verapamil, amantadine, procainamide, and N-methylnicotinamide) inhibited the uptake of [14C]YM155 to a similar extent among the five cell lines. The half-maximal inhibitory concentration values (IC50) of several compounds for the uptake of [14C]YM155 into PC-3 differed from those reported in the literature for human organic cation transporter 1 (OCT1/SLC22A1), OCT2 (SLC22A2), and OCT3 (SLC22A3). To summarize, YM155 was taken up into cancer cells in a carrier-mediated manner and with a similar affinity among all the cancer cell lines tested. An influx transporter(s) may contribute to this process.
Megumi Iwai - One of the best experts on this subject based on the ideXlab platform.
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characterization of human organic cation transporter 1 oct1 slc22a1 and oct2 slc22a2 mediated transport of 1 2 methoxyethyl 2 methyl 4 9 dioxo 3 pyrazin 2 ylmethyl 4 9 dihydro 1h naphtho 2 3 d imidazolium bromide ym155 monobromide a novel small molec
Drug Metabolism and Disposition, 2010Co-Authors: Tsuyoshi Minematsu, Megumi Iwai, Takashi Usui, Kenichi Umehara, Hidetaka KamimuraAbstract:1-(2-Methoxyethyl)-2-methyl-4,9-dioxo-3-(pyrazin-2-ylmethyl)-4,9-dihydro-1 H -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 [ 14 C]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 [ 3 H]1-methyl-4-phenylpyridinium via OCT1, OCT2, and OCT3 with IC 50 values of 23.8, 15.9, and 108 μM, respectively. The time- and saturable concentration-dependent uptake of [ 14 C]YM155 was observed in cells expressing OCT1 and OCT2 with K m 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 IC 50 values of OCT inhibitors and K m 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.
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carrier mediated uptake of 1 2 methoxyethyl 2 methyl 4 9 dioxo 3 pyrazin 2 ylmethyl 4 9 dihydro 1h naphtho 2 3 d imidazolium bromide ym155 monobromide a novel small molecule survivin suppressant into human solid tumor and lymphoma cells
Drug Metabolism and Disposition, 2009Co-Authors: Tsuyoshi Minematsu, Megumi Iwai, Kenji Sugimoto, Nobuaki Shirai, Takahito Nakahara, Takashi Usui, Hidetaka KamimuraAbstract: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 the human hormone refractory prostate carcinoma cell line PC-3. In this study, radioluminographic determination of the in vivo distribution of radioactivity after administration of [14C]YM155 to PC-3-xenografted nude mice revealed a relatively high level of radioactivity in the PC-3 xenograft. Therefore, the uptake of [14C]YM155 was further characterized in vitro using PC-3, lung cancer (Calu-6 and NCI-H358), malignant melanoma (A375 and SK-MEL-5), and non-Hodgkin9s lymphoma (RL and Ramos) cell lines. The uptake of [14C]YM155 in these cell lines was dependent on incubation time, temperature, and drug concentration. The Michaelis-Menten constant values were similar among the seven cell lines (0.189–0.367 μM). The effects of various compounds on the uptake of [14C]YM155 were tested in PC-3, Calu-6, A375, RL, and Ramos cell lines. Of the compounds tested, the cationic transporter substrates/inhibitors (tetraethylammonium, 1-methyl-4-phenylpyridium, cimetidine, prazosin, corticosterone, verapamil, amantadine, procainamide, and N-methylnicotinamide) inhibited the uptake of [14C]YM155 to a similar extent among the five cell lines. The half-maximal inhibitory concentration values (IC50) of several compounds for the uptake of [14C]YM155 into PC-3 differed from those reported in the literature for human organic cation transporter 1 (OCT1/SLC22A1), OCT2 (SLC22A2), and OCT3 (SLC22A3). To summarize, YM155 was taken up into cancer cells in a carrier-mediated manner and with a similar affinity among all the cancer cell lines tested. An influx transporter(s) may contribute to this process.
