Differential Substrate and Inhibitory Activities of Ranitidine and Famotidine toward Human Organic Cation Transporter 1 (hOCT1; SLC22A1), hOCT2 (SLC22A2), and hOCT3 (SLC22A3)

Abstract

Human organic cation transporters (hOCTs) are expressed in organs of drug absorption and elimination and play an important role in the uptake and elimination of xenobiotics. The purpose of this study was to evaluate the substrate and inhibitory activity of the H 2 -receptor antagonists ranitidine and famotidine toward hOCTs and to determine the hOCT isoforms involved in the absorption and elimination of these compounds in humans. Inhibition and substrate specificity of hOCT1, hOCT2, and hOCT3 for ranitidine and famotidine were elucidated in cRNA-injected Xenopus laevis oocytes. Ranitidine and famotidine exhibited similarly potent inhibition of [ 3 H]1-methyl-4-phenyl pyridinium uptake into hOCT1-expressing (IC 50 ϭ 33 and 28 M, respectively) and hOCT2-expressing oocytes (IC 50 ϭ 76 and 114 M, respectively). Famotidine exhibited potent inhibition of hOCT3; in contrast, ranitidine was a moderately weak inhibitor (IC 50 ϭ 6.7 and 290 M, respectively).[ 3 H]Ranitidine uptake was stimulated by hOCT1 (K m ϭ 70 Ϯ 9 M) and to a much smaller extent by hOCT2. No stimulation of [ 3 H]ranitidine uptake was observed in hOCT3-expressing oocytes. trans-Stimulation and electrophysiology studies suggested that famotidine also is an hOCT1 substrate and exhibits poor or no substrate activity toward hOCT2 and hOCT3. Thus, hOCT1, which is expressed in the intestine and liver, is likely to play a major role in the intestinal absorption and hepatic disposition of ranitidine and famotidine in humans, whereas hOCT2, the major isoform present in the kidney, may play only a minor role in their renal elimination. Famotidine seems to be one of the most potent inhibitors of hOCT3 yet identified.The H 2 -receptor antagonists ranitidine and famotidine (Fig.

Discovery of Competitive and Noncompetitive Ligands of the Organic Cation Transporter 1 (OCT1; SLC22A1)

“…The inability of HTS to identify some of the previously reported ligands can be explained by their OCT1 affinity, which is much weaker than that of ASP + . For example, the reported IC 50 values of cimetidine and metformin for inhibition of OCT1-mediated transport of YM155 and MPP + were 149 and 1230 μM, respectively, 27,28 and the IC 50 of thiamine was determined to be 4.1 mM ( Figure S1). Because our HTS assay measured inhibition of OCT1 activity by test compounds at 20 μM, it was unable to identify ligands such as cimetidine, metformin, and thiamine.…”

Transport of Dicationic Drugs Pentamidine and Furamidine by Human Organic Cation Transporters

“…In brief, cells were seeded in 96-well plates at 3000 cells/well. After 24 h, cells were exposed to different concentrations of diamidines in the presence or absence of 1 mM ranitidine, an OCT1 inhibitor (Bourdet et al, 2005), for 24 h. Drug-containing medium was replaced with fresh medium, and cells were incubated for an additional 24 h. Alamar Blue reagent was added and incubated for 4 h. The samples were read in a microplate reader set at 544-nm excitation wavelength and 584-nm emission wavelength. The IC 50 values were obtained by fitting F, the percentage of the maximal cell growth at different drug concentrations, to the equation…”

“…In humans, human (h) OCT1 is predominantly expressed in the liver, whereas hOCT2 is mainly expressed in the kidney (Gorboulev et al, 1997;Zhang et al, 1997). OCTs interact with many drugs, including the H2 antagonist ranitidine (Bourdet et al, 2005), the antidiabetic drug metformin (Wang et al, 2002), and the anticancer drug oxaliplatin (Yokoo et al, 2007). The majority of OCT substrates are monovalent and comparatively small cations, the socalled type I organic cations (Meijer et al, 1999;Wright, 2005) as exemplified by the prototypical substrates tetraethylammonium (TEA) and the neurotoxin 1-methyl-4-phenylpyridinium (MPP ϩ ) (Koepsell et al, 2007).…”

Antiulcerogenic Efficacy of Ethanolic Extract of Vitis Vinifera Leaves in Rats

“…The method was carried out as described by [32]. The following concentrations of VVE and vitamin C (standard antioxidant) concentrations were prepared 10,20,30,40,50,60,70, and 80 mg/ml in each tube. 2 ml of DPPH; (250 mm DPPH/200 ml methanol) then added the certain concentration of each extract, and adjust the final volume to be 4 ml with methanol.…”

“…Treatment with RAN has an ability to antagonize the binding of histamine to the H2-receptor on the parietal cells. Therefore, it can counter the effect of indomethacin on acid secretion [20,21]. Since the clinical evaluation of synthetic drugs has shown the incidence of some adverse effects, treatment with natural products is now considered as an alternative approach for the treatment of gastric ulcer.…”