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Dhiren R. Thakker - One of the best experts on this subject based on the ideXlab platform.
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intestinal absorptive transport of the hydrophilic cation Ranitidine a kinetic modeling approach to elucidate the role of uptake and efflux transporters and paracellular vs transcellular transport in caco 2 cells
Pharmaceutical Research, 2006Co-Authors: David L Bourdet, Gary M Pollack, Dhiren R. ThakkerAbstract:The mechanism of intestinal drug transport for hydrophilic cations such as Ranitidine is complex, and evidence suggests a role for carrier-mediated apical (AP) uptake and saturable paracellular mechanisms in their overall absorptive transport. The purpose of this study was to develop a model capable of describing the kinetics of cellular accumulation and transport of Ranitidine in Caco-2 cells, and to assess the relative contribution of the transcellular and paracellular routes toward overall Ranitidine transport. Cellular accumulation and absorptive transport of Ranitidine were determined in the absence or presence of uptake and efflux inhibitors and as a function of concentration over 60 min in Caco-2 cells. A three-compartment model was developed, and parameter estimates were utilized to assess the expected relative contribution from transcellular and paracellular transport. Under all conditions, Ranitidine absorptive transport consisted of significant transcellular and paracellular components. Inhibition of P-glycoprotein decreased the AP efflux rate constant (k 21) and increased the relative contribution of the transcellular transport pathway. In the presence of quinidine, both the AP uptake rate constant (k 12) and k 21 decreased, resulting in a predominantly paracellular contribution to Ranitidine transport. Increasing the Ranitidine donor concentration decreased k 12 and the paracellular rate constant (k 13). No significant changes were observed in the relative contribution of the paracellular and transcellular routes as a function of Ranitidine concentration. These results suggest the importance of uptake and efflux transporters as determinants of the relative contribution of transcellular and paracellular transport for Ranitidine, and provide evidence supporting a concentration-dependent paracellular transport mechanism. The modeling approach developed here may also be useful in estimating the relative contribution of paracellular and transcellular transport for a wide array of drugs expected to utilize both pathways.
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saturable absorptive transport of the hydrophilic organic cation Ranitidine in caco 2 cells role of ph dependent organic cation uptake system and p glycoprotein
Pharmaceutical Research, 2006Co-Authors: David L Bourdet, Dhiren R. ThakkerAbstract:The purpose of this work was to investigate the involvement of carrier-mediated apical (AP) uptake and efflux mechanisms in the absorptive intestinal transport of the hydrophilic cationic drug Ranitidine in Caco-2 cells. Absorptive transport and AP uptake of Ranitidine were determined in Caco-2 cells as a function of concentration. Permeability of Ranitidine in the absorptive and secretory directions was assessed in the absence or presence of the P-glycoprotein (P-gp) inhibitor, GW918. Characterization of the uptake mechanism was performed with respect to inhibitor specificity, pH, energy, membrane potential, and Na+ dependence. Efflux from preloaded monolayers was evaluated over a range of concentrations and in the absence or presence of high extracellular Ranitidine concentrations. Saturable absorptive transport and AP uptake of Ranitidine were observed with K m values of 0.27 and 0.45 mM, respectively. The Ranitidine absorptive permeability increased and secretory permeability decreased upon inhibition of P-gp. AP Ranitidine uptake was inhibited in a concentration-dependent fashion by a diverse set of organic cations including tetraethylammonium, 1-methyl-4-phenylpyridinium, famotidine, and quinidine. AP Ranitidine uptake was pH and membrane potential dependent and reduced under conditions that deplete metabolic energy. Efflux of [3H]Ranitidine across the basolateral membrane was neither saturable as a function of concentration nor trans stimulated by unlabeled Ranitidine. Saturable absorptive transport of Ranitidine in Caco-2 cells is partially mediated via a pH-dependent uptake transporter for organic cations and is subject to attenuation by P-gp. Inhibition and driving force studies suggest the uptake carrier exhibits similar properties to cloned human organic cation transporters. The results also imply Ranitidine transport is not solely restricted to the paracellular space.
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differential substrate and inhibitory activities of Ranitidine and famotidine toward human organic cation transporter 1 hoct1 slc22a1 hoct2 slc22a2 and hoct3 slc22a3
Journal of Pharmacology and Experimental Therapeutics, 2005Co-Authors: David L Bourdet, John B Pritchard, Dhiren R. ThakkerAbstract: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 H2-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 [3H]1-methyl-4-phenyl pyridinium uptake into hOCT1-expressing (IC50 = 33 and 28 μM, respectively) and hOCT2-expressing oocytes (IC50 = 76 and 114 μM, respectively). Famotidine exhibited potent inhibition of hOCT3; in contrast, Ranitidine was a moderately weak inhibitor (IC50 = 6.7 and 290 μM, respectively). [3H]Ranitidine uptake was stimulated by hOCT1 ( K m = 70 ± 9 μM) and to a much smaller extent by hOCT2. No stimulation of [3H]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.
S.-d. Xiao - One of the best experts on this subject based on the ideXlab platform.
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one week regimens containing Ranitidine bismuth citrate furazolidone and either amoxicillin or tetracycline effectively eradicate helicobacter pylori a multicentre randomized double blind study
Alimentary Pharmacology & Therapeutics, 2001Co-Authors: D.-z. Zhang, X.-c. Fang, S.-d. XiaoAbstract:Background: The metronidazole resistance of Helicobacter pylori strains has increased rapidly. Aim: To evaluate the efficacy and safety of new 1-week regimens containing Ranitidine bismuth citrate, furazolidone and either amoxicillin or tetracycline. Methods: One hundred and twenty patients with H. pylori-positive inactive duodenal ulcer or non-ulcer dyspepsia diagnosed by endoscopy were recruited randomly to receive one of two regimens for 7 days: Ranitidine bismuth citrate, 350 mg b.d., furazolidone, 100 mg b.d., and either amoxicillin, 1000 mg b.d. (n=60), or tetracycline, 500 mg b.d. (n=60). H. pylori infection was identified by rapid urease testing and histology. 13C-Urea breath test was performed to evaluate the cure of H. pylori infection at least 4 weeks after completion of triple therapy. Results: The eradication rates of H. pylori by Ranitidine bismuth citrate–furazolidone–amoxicillin and Ranitidine bismuth citrate–furazolidone–tetracycline regimens were 82% and 85% (P > 0.05), respectively, by intention-to-treat analysis, and 85% and 91% (P > 0.05), respectively, by per protocol analysis. Adverse effects were mild in both Ranitidine bismuth citrate–furazolidone–amoxicillin and Ranitidine bismuth citrate–furazolidone–tetracycline groups. Conclusions: One-week regimens containing Ranitidine bismuth citrate, furazolidone and amoxicillin or tetracycline are well tolerated and effective for the eradication of H. pylori.
C C Lim - One of the best experts on this subject based on the ideXlab platform.
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roxatidine versus Ranitidine in the treatment of duodenal ulcers a randomized double blind controlled multicentre study in singapore
Journal of Gastroenterology and Hepatology, 1995Co-Authors: K M Fock, J Y Kang, K A Gwee, C C LimAbstract:Roxatidine acetate, a new H2 receptor antagonist, was compared with Ranitidine in the treatment of duodenal ulcers in a double-blind multicentre study. Eighty-four patients with endoscopically proven duodenal ulcer were randomized to receive 150 mg roxatidine acetate or 300 mg Ranitidine at bedtime. Repeat endoscopy was performed after 4 weeks (25-33 days) and if the ulcer had not healed, another endoscopy was performed after a further 4 weeks of treatment. Using per protocol analysis 73.6% of ulcers treated with roxatidine healed at 4 weeks compared to 72.2% of ulcers treated with Ranitidine (P = NS). The healing rates at 8 weeks were 92% with roxatidine and 83.3% with Ranitidine (P = NS). Using equivalence tests, the healing rate of roxatidine was found to be equivalent to that of Ranitidine within a 20% region. Roxatidine users took significantly less antacids than Ranitidine users (P < 0.05). There were no significant adverse effects due to roxatidine or Ranitidine. Roxatidine is a safe effective drug in the treatment of duodenal ulcers with a healing rate comparable to that of Ranitidine.
John R Wood - One of the best experts on this subject based on the ideXlab platform.
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the safety of Ranitidine bismuth citrate in controlled clinical studies
Pharmacoepidemiology and Drug Safety, 1996Co-Authors: Graham A Pipkin, Jane G Mills, Lata Kler, Jonathon S Dixon, John R WoodAbstract:Ranitidine bismuth citrate (PYLORID™, TRITEC®) is a novel drug which heals peptic ulcers and when co-prescribed with either clarithromycin or amoxycillin eradicatesHelicobacter pylori. In controlled clinical studies it was well-tolerated when given alone or when co-prescribed with either antibiotic. Data from 20 clinical studies are reported in this analysis of safety with almost 5000 patients having received Ranitidine bismuth citrate (200, 400, or 800 mg twice daily). The incidence of adverse events reported with this new drug, either alone or with an antibiotic, was not different from or lower than in patients given placebo and was independent of the dose of Ranitidine bismuth citrate tested. Most commonly reported events (>1% of patients) were upper respiratory tract infection, constipation, diarrhoea, nausea and vomiting, dizziness, and headache, the latter being the only event reported by >2% of patients who received Ranitidine bismuth citrate alone. Adverse events considered by the clinical investigator to be adverse reactions occurred with a similar frequency amongst patients given Ranitidine bismuth citrate (8%), Ranitidine hydrochloride (6%), or placebo (6%). The incidence of adverse reactions was greater when co-prescribed with amoxycillin (11%) or clarithromycin (20%) although it was not different from that noted with the antibiotics alone. Serious adverse events were reported in similar proportions of patients given placebo, Ranitidine bismuth citrate alone or with an antibiotic, and Ranitidine hydrochloride (range: <1–2%). The safety profile of Ranitidine bismuth citrate was thus comparable to that of Ranitidine hydrochloride (ZANTAC™), a drug with a well-established record of safety in clinical use.
David L Bourdet - One of the best experts on this subject based on the ideXlab platform.
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intestinal absorptive transport of the hydrophilic cation Ranitidine a kinetic modeling approach to elucidate the role of uptake and efflux transporters and paracellular vs transcellular transport in caco 2 cells
Pharmaceutical Research, 2006Co-Authors: David L Bourdet, Gary M Pollack, Dhiren R. ThakkerAbstract:The mechanism of intestinal drug transport for hydrophilic cations such as Ranitidine is complex, and evidence suggests a role for carrier-mediated apical (AP) uptake and saturable paracellular mechanisms in their overall absorptive transport. The purpose of this study was to develop a model capable of describing the kinetics of cellular accumulation and transport of Ranitidine in Caco-2 cells, and to assess the relative contribution of the transcellular and paracellular routes toward overall Ranitidine transport. Cellular accumulation and absorptive transport of Ranitidine were determined in the absence or presence of uptake and efflux inhibitors and as a function of concentration over 60 min in Caco-2 cells. A three-compartment model was developed, and parameter estimates were utilized to assess the expected relative contribution from transcellular and paracellular transport. Under all conditions, Ranitidine absorptive transport consisted of significant transcellular and paracellular components. Inhibition of P-glycoprotein decreased the AP efflux rate constant (k 21) and increased the relative contribution of the transcellular transport pathway. In the presence of quinidine, both the AP uptake rate constant (k 12) and k 21 decreased, resulting in a predominantly paracellular contribution to Ranitidine transport. Increasing the Ranitidine donor concentration decreased k 12 and the paracellular rate constant (k 13). No significant changes were observed in the relative contribution of the paracellular and transcellular routes as a function of Ranitidine concentration. These results suggest the importance of uptake and efflux transporters as determinants of the relative contribution of transcellular and paracellular transport for Ranitidine, and provide evidence supporting a concentration-dependent paracellular transport mechanism. The modeling approach developed here may also be useful in estimating the relative contribution of paracellular and transcellular transport for a wide array of drugs expected to utilize both pathways.
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saturable absorptive transport of the hydrophilic organic cation Ranitidine in caco 2 cells role of ph dependent organic cation uptake system and p glycoprotein
Pharmaceutical Research, 2006Co-Authors: David L Bourdet, Dhiren R. ThakkerAbstract:The purpose of this work was to investigate the involvement of carrier-mediated apical (AP) uptake and efflux mechanisms in the absorptive intestinal transport of the hydrophilic cationic drug Ranitidine in Caco-2 cells. Absorptive transport and AP uptake of Ranitidine were determined in Caco-2 cells as a function of concentration. Permeability of Ranitidine in the absorptive and secretory directions was assessed in the absence or presence of the P-glycoprotein (P-gp) inhibitor, GW918. Characterization of the uptake mechanism was performed with respect to inhibitor specificity, pH, energy, membrane potential, and Na+ dependence. Efflux from preloaded monolayers was evaluated over a range of concentrations and in the absence or presence of high extracellular Ranitidine concentrations. Saturable absorptive transport and AP uptake of Ranitidine were observed with K m values of 0.27 and 0.45 mM, respectively. The Ranitidine absorptive permeability increased and secretory permeability decreased upon inhibition of P-gp. AP Ranitidine uptake was inhibited in a concentration-dependent fashion by a diverse set of organic cations including tetraethylammonium, 1-methyl-4-phenylpyridinium, famotidine, and quinidine. AP Ranitidine uptake was pH and membrane potential dependent and reduced under conditions that deplete metabolic energy. Efflux of [3H]Ranitidine across the basolateral membrane was neither saturable as a function of concentration nor trans stimulated by unlabeled Ranitidine. Saturable absorptive transport of Ranitidine in Caco-2 cells is partially mediated via a pH-dependent uptake transporter for organic cations and is subject to attenuation by P-gp. Inhibition and driving force studies suggest the uptake carrier exhibits similar properties to cloned human organic cation transporters. The results also imply Ranitidine transport is not solely restricted to the paracellular space.
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differential substrate and inhibitory activities of Ranitidine and famotidine toward human organic cation transporter 1 hoct1 slc22a1 hoct2 slc22a2 and hoct3 slc22a3
Journal of Pharmacology and Experimental Therapeutics, 2005Co-Authors: David L Bourdet, John B Pritchard, Dhiren R. ThakkerAbstract: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 H2-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 [3H]1-methyl-4-phenyl pyridinium uptake into hOCT1-expressing (IC50 = 33 and 28 μM, respectively) and hOCT2-expressing oocytes (IC50 = 76 and 114 μM, respectively). Famotidine exhibited potent inhibition of hOCT3; in contrast, Ranitidine was a moderately weak inhibitor (IC50 = 6.7 and 290 μM, respectively). [3H]Ranitidine uptake was stimulated by hOCT1 ( K m = 70 ± 9 μM) and to a much smaller extent by hOCT2. No stimulation of [3H]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.
