Eur J Clin Pharmacol. 1994;46(3):253-9.
Site-dependent small intestinal absorption of ranitidine.

Gramatte T, el Desoky E, Klotz U.

Institute of Clinical Pharmacology, Faculty of Medicine, Technical University, Dresden, Germany.

The site-dependent, small intestinal absorption characteristics of ranitidine were estimated by the intestinal steady state perfusion technique (triple lumen tubing system) combined with simultaneous measurement of serum concentrations of ranitidine. Ranitidine 150 mg.l-1 was perfused at 10 ml.min-1 for 180 min in different sites of the small intestine between 65-250 cm beyond the teeth. Each of 9 healthy, male volunteers was examined twice, using perfusion sites in different regions of the small intestine to permit intraindividual comparisons. The absorption rates (micrograms.30 cm-1.min-1) calculated from intestinal samples showed distinct site-dependence; the highest rates (medians 160-923 micrograms.30 cm-1.min-1) were found in the most proximal region (duodenojejunal junction), and the most distal perfusion sites (distal jejunum/ileum) showed median rates from 193 to 265 micrograms.30 cm-1.min-1. In both of these regions there was a significant positive correlation between the net intestinal water flux and the movement of ranitidine. Within the mid-jejunum, every subject showed marked secretion of ranitidine into the gut lumen (medians -338 to -124 micrograms.30 cm-1.min-1), and in this region there was no influence of water flux on ranitidine movement. The intraluminal results were confirmed by the corresponding site-dependent areas under the serum concentration-time curves (AUC), which decreased with the distance of the perfusion site from the teeth. After the more distal perfusions individual AUCs amounted to 64-16% of the AUCs obtained after more proximal applications. The results demonstrate the small intestine as the site of a gradient of absorption of ranitidine.(ABSTRACT TRUNCATED AT 250 WORDS)

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Res Commun Chem Pathol Pharmacol. 1993 Feb;79(2):185-93.
Inhibition of cholinesterases by histamine 2 receptor antagonist drugs.

Laine-Cessac P, Turcant A, Premel-Cabic A, Boyer J, Allain P.

Laboratoire de Pharmacologie et Toxicologie, Centre Hospitalier Universitaire, Angers, France.

Many studies have demonstrated that histamine 2 receptor antagonists (H2RA) have in vitro anticholinesterase effects, but discrepancies about type and potency of this inhibitory effect exist among published results. Moreover, cholinesterase inhibition has not been shown in patients receiving H2RA. These discrepancies led us to study the in vitro antibutyryl- and in vitro antiacetylcholinesterase activities of ranitidine, cimetidine, nizatidine comparatively to pyridostigmines. Plasma cholinesterase activity (PCEA), erythrocyte cholinesterase activity (ECEA) and plasma ranitidine levels were measured in six patients before and during continuous IV infusion (150 or 200 mg/d) of ranitidine. Our in vitro results confirm the weak anticholinesterase activity of H2RA. Ranitidine is the most potent inhibitor of butyrylcholinesterase (Ki = 61 microM). Ranitidine and nizatidine are the most potent inhibitors of acetylcholinesterase (Ki' = 2.1 microM, Ki' = 5.1 microM, respectively) but one thousand times less effective than pyridostigmine (Ki = 0.003 microM). The results in patients show no statistically significant difference between PCEA and ECEA measured before and during ranitidine infusion (plasma ranitidine levels between 0.31 and 1.25 microM).

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Pancreas. 1993 Jul;8(4):494-8.
Fat absorption and gastroenteric pH profile in postsurgical pancreatic insufficiency: role of the association of H2-receptor antagonists with pancreatic enzymes.

Braga M, Zerbi A, Malesci A, Dal Cin S, Valentini A, Tacconi M, Erenbourg L, Paganelli M, Di Carlo V.

Department of Surgery, Scientific Institute San Raffaele, Milan, Italy.

The complete control of steatorrhea in post-surgical exocrine pancreatic insufficiency is difficult. The aim of this study was to evaluate the effect of the association of ranitidine with pancrelipase om fecal fat excretion in patients who had undergone a pancreatoduodenectomy with suppression of the exocrine pancreatic secretion by Neoprene injection. Ten patients were studied 1 year after surgery. Steatorrhea was measured as an integrated test of 3-day stools, while patients were kept on a diet of 100 g lipid/day, with their usual enzyme supplementation therapy (16,050 USP units of lipase/meal). A basal 24-h gastroenteric pH profile was also obtained. In the following month, patients had ranitidine (150 mg twice a day) in addition to pancrelipase. Then steatorrhea and gastroenteric pH were reassessed. Mean fecal fat was 26.9 (SD 13.7) g/day without ranitidine and 30.5 (SD 13.9) g/day during combined treatment. Body weight and nutritional parameters did not show any significant variation after ranitidine administration. Even in the absence of ranitidine, postprandial gastroenteric pH values were always > 4; the H2-receptor antagonist only reduced fasting gastric acidity. In conclusion, the gastroenteric pH and fecal fat determinations showed that ranitidine is not useful in patients with total postsurgical exocrine pancreatic insufficiency.

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Dig Dis Sci. 1993 Oct;38(10):1857-65.
Parenteral control of gastric acid hypersecretion in patients with Zollinger-Ellison syndrome.

Vinayek R, Hahne WF, Euler AR, Norton JA, Jensen RT.

Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland 20892.

Parenteral control of gastric acid hypersecretion in patients with Zollinger-Ellison syndrome is increasingly required; however, existing methods of determining the required dose are cumbersome and not applicable in all centers. A previous study suggested that the required parenteral dose of histamine H2-receptor antagonists correlated with the previous oral dose. In the present study, in 31 patients with Zollinger-Ellison syndrome we evaluated the hypothesis that an effective parenteral histamine H2-receptor antagonist dose could be predicted from the previous oral dose. Twenty-three patients were taking oral ranitidine (mean 1.3 g/day), six patients famotidine (152 mg/day), and two patients cimetidine (1.8 g/day). Each patient was treated with a continuous intravenous infusion of the equivalent dose of ranitidine (mean dose 1 mg/kg/hr with 35% requiring 0.5 mg/kg/hr, 49% 1 mg/kg/hr, 3% 1.5 mg/kg/hr, 10% 2 mg/kg/hr, and 3% 2.5 mg/kg/hr. This dose of ranitidine acutely controlled acid secretion (< 10 meq/hr) in all patients. To evaluate long-term efficacy and safety, 20 patients were maintained on this dose through the peri- and postoperative periods. Mean duration was 7.1 days with 25% treated 3-5 days, 40% 6-8 days, 30% 8-10 days, and 5% > 10 days. The predicted dose continued to control acid secretion in 95% of patients with one patient requiring one dose adjustment. No biochemical, clinical, or hematological toxicity was seen, although ranitidine was stopped in one patient because of skin rash. These results demonstrate that the parenteral dose of ranitidine required to control acid secretion in patients with Zollinger-Ellison syndrome can be predicted from the oral dose.(ABSTRAC




Equine Vet J. 1993 Sep;25(5):417-21.
Measurement of 24-h gastric pH using an indwelling pH electrode in horses unfed, fed and treated with ranitidine.

Murray MJ, Schusser GF.

Marion duPont Scott Equine Medical Center, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Leesburg 22075.

A glass combined pH-reference electrode was placed in the stomachs of 5 adult horses and pH was recorded every 6 mins for 24 h while (1) feed and all bedding materials were withheld for 24 h (unfed), (2) horses had free access to Timothy grass hay for 24 h (fed), and (3) horses had free access to Timothy grass hay and were treated with ranitidine, 6.6 mg/kg body weight, orally, every 8 h for 48 h (fed + ranitidine). There was a significant (P = 0.007) difference in median 24-h gastric pH amongst the 3 protocols, the value being 3.1 in fed horses and 1.55 in unfed horses (P = 0.05) and 4.6 in fed + ranitidine horses (P = 0.05 compared with fed horses). The percentage of pH readings < 2.0 was significantly greater (P = 0.05) in unfed (76%) than in fed (30%) horses, and in fed horses than in fed + ranitidine (9%) horses. The percentage of readings > 2.0, 3.0, 4.0, 5.0 and 6.0 were each significantly (P = 0.05) greater in fed + ranitidine horses than in fed horses, and in fed than in unfed horses. There was no difference (P = 0.13) between median gastric pH values from different times of day in unfed horses (00:00 to 06:00 h, 1.5; 06:00 to 12:00 h, 1.6; 12:00 to 18:00 h, 1.7; and 18:00 to 24:00 h, 1.5). We conclude that gastric acidity is greatest when horses do not have access to feed material and that ranitidine effectively suppresses gastric acidity in horses under conditions of free access to hay.

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Biochim Biophys Acta. 1993 Jun 30;1177(3):245-52.
Gastrin action on aminopyrine accumulation in isolated pig parietal cells requires cAMP.

Cabero JL, Li ZQ, Mardh S.

Department of Medical and Physiological Chemistry, Uppsala University, Sweden.

The mechanism of action of gastrin on pig parietal cells was investigated. The aminopyrine accumulation technique was used to estimate acid production in gastric mucosal cells, containing 10-20% parietal cells, and in enriched parietal cells, containing 65-95% parietal cells. The gastrin analogue pentagastrin stimulated aminopyrine accumulation in a dose-dependent fashion irrespective of the proportion of non-parietal cells present. The apparent EC50 for pentagastrin was 5 nM and the maximally effective concentration was 100 nM. The histamine H2-receptor antagonist ranitidine did not affect the action of pentagastrin. The stimulatory effects of various doses of histamine on aminopyrine accumulation in highly enriched parietal cells were potentiated by the inclusion of 100 nM pentagastrin in the incubation medium. In another series of experiments using mucosal cells, the action of effective doses of pentagastrin were potentiated by the phosphodiesterase inhibitor isobutylmethyl xanthine (IBMX), which alone elicited an aminopyrine accumulation equal to 50% of that obtained by 100 microM histamine. When ranitidine (100 microM) was included, the action of IBMX was almost completely abolished. However, the dose-response curve for pentagastrin in the presence of ranitidine plus IBMX was similar to that obtained in the absence of IBMX. Dibutyryl-cAMP (DBcAMP, 1 mM) in the presence of ranitidine (100 microM) also potentiated the action of all effective doses of pentagastrin on mucosal cells. The protein kinase A inhibitor Rp-cAMPS, present at 500 microM in the incubation medium, significantly reduced the action of each effective concentration of pentagastrin on aminopyrine accumulation in enriched parietal cells. These results in pig parietal cells were interpreted as




Pol Tyg Lek. 1993 Mar 15-29;48(11-13):271-3.
[Evaluation of microsomal liver enzyme function in patients with duodenal ulcer treated with ranitidine]

[Article in Polish]

Piotrowski J, Piotrowska E.

Katedry i Kliniki Chorob Wewnetrznych i Zawodowych, Zabrzu.

Functioning of hepatocytes has been assessed with respiratory test with aminopyrine labelled with 14C radioisotope in patients with duodenal ulcer treated with ranitidine. Reversibility of changes in liver microsomal system at different intervals after the completion of therapy has also been evaluated. Altogether 30 patients with duodenal ulcer treated with ranitidine have been examined: prior to the treatment--group Ia, after one day of ranitidine administration--group Ib, within 4 weeks of therapy--group Ic, within 8 weeks of therapy--group Id, and one week after the completion of the treatment--group Ie, as well as after a 4-week follow-up period--group If. Significant decrease in the results of respiratory test has been noted in patients treated with ranitidine after both four and eight weeks. Activity of liver mono-oxidases approached baseline values after one week following the completion of therapy. The results of routine liver functioning tests in all patients of groups I and II have been within normal values. The obtained results suggest that patients treated with ranitidine should cautiously be given other medicines, especially those affecting liver functioning or metabolized in the liver.

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Crit Care Med. 1993 Dec;21(12):1850-5.
Control and variability of gastric pH in critically ill children.

Gedeit RG, Weigle CG, Havens PL, Werlin SL.

Department of Pediatrics, Medical College of Wisconsin, Milwaukee.

OBJECTIVES: To determine the effect of illness severity and acute central nervous system injury on the control and variability of gastric pH in pediatric intensive care unit (ICU) patients receiving ranitidine. DESIGN: Prospective, descriptive study. SETTING: Pediatric ICU of a children's hospital. PATIENTS: Fourteen pediatric ICU patients. INTERVENTIONS: Ranitidine (4 mg/kg/day) was administered to all patients. MEASUREMENTS AND MAIN RESULTS: Patients enrolled in the study were divided into two groups based on illness type and severity. Illness severity was measured by the Pediatric Risk of Mortality (PRISM) score, with a PRISM score of > or = 20 defining severe illness. Illness type was designated as central nervous system or noncentral nervous system. Gastric pH was continuously monitored in all patients using an intragastric, pH-sensitive electrode. Poor control of gastric pH was defined as a pH of < 4.0 for > 20% of the time monitored. The statistical significance of the differences between groups was measured using the Wilcoxon two-sample test or Fisher's exact test. Patients with severe illness or acute central nervous system injury had a lower mean gastric pH than all other patients (4.6 vs. 6.4; p = .008) and spent more time with a gastric pH of < 4.0 than other patients (47.5% of time monitored vs. 12.5% of time monitored; p = .003). Poor control of gastric pH occurred in 100% of patients with severe illness or acute central nervous system injury, while only 20% of the remaining patients had poor control of gastric pH (p = .01). Using power-spectrum analysis to evaluate gastric pH variability, gastric pH in patients receiving bolus ranitidine was more variable than gastric pH in patients receiving ranitidine continuously (p = .045). Illness severity or typ




Pharm Res. 1993 Dec;10(12):1722-5.
Mechanism of intestinal absorption of ranitidine and ondansetron: transport across Caco-2 cell monolayers.

Gan LS, Hsyu PH, Pritchard JF, Thakker D.

Department of Drug Metabolism, Glaxo Inc., Research Triangle Park, North Carolina 27709.

We have investigated the transport of ranitidine and ondansetron across the Caco-2 cell monolayers. The apparent permeability co-efficients (Papp) were unchanged throughout the concentration range studied, indicating a passive diffusion pathway across intestinal mucosa. No metabolism was observed for ranitidine and ondansetron during the incubation with Caco-2 cell monolayers. Papp values for ranitidine and ondansetron (bioavailability of 50 and approximately 100% in humans, respectively) were 1.03 +/- 0.17 x 10(-7) and 1.83 +/- 0.055 x 10(-5) cm/sec, respectively. The Papp value for ranitidine was increased by 15- to 20-fold in a calcium-free medium or in the transport medium containing EDTA, whereas no significant change occurred with ondansetron, indicating that paracellular passive diffusion is not rate determining for ondansetron. Uptake of ondansetron by Caco-2 cell monolayers was 20- and 5-fold higher than that of ranitidine when the uptake study was carried out under sink conditions and at steady state. These results suggest that ranitidine and ondansetron are transported across Caco-2 cell monolayers predominantly via paracellular and transcellular pathways, respectively.

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