J Pharm Pharmacol. 1985 Mar;37(3):196-8.
The inhibitory effects of ranitidine and cimetidine on propranolol elimination by the rat isolated perfused liver.

Jones DB, Ching MS, Morgan DJ, Anderson JD, Smallwood RA.

The effect of low (50 micrograms) and high (1 mg) doses of the histamine H2-receptor antagonists cimetidine and ranitidine on the first pass extraction of propranolol was studied in the rat isolated perfused liver. Both low and high dose cimetidine increased the area under the perfusate propranolol concentration time curve (AUC) 4 to 5-fold. Although low dose ranitidine did not alter propranolol AUC, high dose ranitidine increased it to the same extent as cimetidine. These results indicate that ranitidine has a clear propensity for microsomal inhibition, but one which is unlikely to be manifest at therapeutic dosage.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2858568&dopt=Abstract ranitidine






Res Commun Chem Pathol Pharmacol. 1985 Mar;47(3):461-4.
Effects of cimetidine and ranitidine on trimethadione metabolism in the rat.

Tanaka E, Misawa S.

Pretreatment of rats with cimetidine (100 mg/kg, i.p.) resulted in a prolongation of TMO half-life, an increase in the area under the curve (AUC) and a decrease of clearance (Cl), whereas in the rats pretreated with ranitidine (120 mg/kg, i.p.), these parameters were not changed. The apparent volume of distribution (Vd) values were not changed by either of the drugs as compared to controls. Activities of hepatic cytochrome P-450-dependent metabolizing enzymes such as aminopyrine- and TMO N-demethylase and aniline hydroxylase activity were decreased by pretreatment of rats with cimetidine, whereas in the rats pretreated with ranitidine, these enzyme activities were not changed. Cytochrome P-450 contents were not changed by either of the drugs as compared to controls. The inhibition manner of aminopyrine- and TMO N-demethylase activities in the rats pretreated with cimetidine was noncompetitive. These results indicate, together with the previous findings, that cimetidine treatment inhibited TMO metabolism, but ranitidine did not.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3992022&dopt=Abstract ranitidine






Biochem Pharmacol. 1985 May 1;34(9):1415-21.
The effect of cimetidine and ranitidine on paracetamol glucuronidation and sulphation in cultured rat hepatocytes.

Emery S, Oldham HG, Norman SJ, Chenery RJ.

Cimetidine and ranitidine have been investigated for their ability to inhibit conjugation reactions in cultures of rat hepatocytes. Neither compound had any appreciable effect on rates of paracetamol sulphation. However, both cimetidine and ranitidine inhibited the glucuronidation of paracetamol in a dose-dependent manner. No adverse effects on cellular viability were noted utilizing enzyme leakage (lactic dehydrogenase) or protein synthesis measurements. The kinetics of inhibition by ranitidine were studied in more detail. At 0.25 mM ranitidine, the inhibition appeared to be purely competitive. However, at higher concentrations decreases in Vappmax were noted suggesting a more complex mechanism of inhibition. The relevance to inhibition in vivo by cimetidine and ranitidine and possible interactions between paracetamol and these histamine H2-receptor antagonists are discussed.

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Hepatology. 1985 May-Jun;5(3):480-7.
Ranitidine-acetaminophen interaction: effects on acetaminophen-induced hepatotoxicity in Fischer 344 rats.

Leonard TB, Morgan DG, Dent JG.

Cimetidine has been shown to protect against acetaminophen-mediated hepatotoxicity in both rats and mice. In contrast to cimetidine, ranitidine recently has been determined to potentiate the hepatotoxic action of acetaminophen in Fischer 344 rats. The present studies were designed to characterize this ranitidine-acetaminophen interaction. Acetaminophen administration (750 mg per kg, p.o.) to F344 rats produced maximal hepatic necrosis, 24 hr after treatment, as assessed by SGPT activity and histopathology. Ranitidine pretreatment 30 min prior to acetaminophen treatment increased the toxicity but did not alter its course. Ranitidine administration (50 mg per kg) enhanced acetaminophen hepatotoxicity throughout the toxic dose range of acetaminophen (600 to 1,000 mg per kg) and potentiation of acetaminophen hepatotoxicity by ranitidine was dose-dependent. Maximal increases were observed at 50 mg per kg ranitidine whereas, doses of ranitidine greater than 100 mg per kg inhibited acetaminophen toxicity. SGPT data were corroborated by histopathologic evaluation. Ranitidine was not hepatotoxic when administered alone (500 mg per kg), or following glutathione depletion, or after induction of hepatic mixed-function oxidase activity. The results obtained in these studies support the suggestion that, at high doses (greater than 100 mg per kg), ranitidine reduces acetaminophen hepatotoxicity by reducing metabolic activation, while at lower doses ranitidine potentiates acetaminophen hepatotoxicity. Inhibition by ranitidine of acetaminophen conjugation is proposed as a possible mechanism of this potentiation.

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J Chromatogr. 1985 Apr 17;323(1):143-52.
Qualitative and quantitative analysis of ranitidine and its metabolites by high-performance liquid chromatography-mass spectrometry.

Lant MS, Martin LE, Oxford J.

Reversed-phase high-performance liquid chromatography systems for the separation of ranitidine and its metabolites ranitidine-N-oxide, ranitidine-S-oxide, and desmethylranitidine have been developed for use in high-performance liquid chromatography-mass spectrometry. A direct liquid introduction-high-performance liquid chromatography-mass spectrometry system to analyse qualitatively and quantitatively solutions containing ranitidine and its metabolites by reversed-phase chromatography is described. A sample of urine collected from a subject given an oral dose of 75 mg of ranitidine and 75 mg of tris-deuterated ranitidine was analysed by this system. Ranitidine and its metabolites were identified by the ion doublets in the mass spectra which were 3 a.m.u. apart.

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Agents Actions. 1985 Apr;16(3-4):183-6.
The effect of stimulation and blocking of histamine H2 receptors on the turnover of the serotonin in different parts of the alimentary tract and the brain of the rat.

Skrzydlo-Radomanska B, Pokora J, Kleinrok Z, Radwan P.

In the experiments performed on Wistar rats it was found that histamine (0.05 and 0.5 mg/kg i.p.) caused an acceleration of the turnover of serotonin (5-HT) in the stomach. After the lowest dose of ranitidine (3 mg/kg i.p.) a decrease in the rate of 5-HT turnover in the stomach was observed, whereas the higher doses (15.0 and 30 mg/kg i.p.) accelerated the turnover of this amine. In the duodenum, both doses of histamine accelerated the turnover of 5-HT, however, ranitidine in all doses induced a reduction in the rate of 5-HT turnover in this part of the alimentary tract. In the intestine, both doses of histamine enhanced the turnover of 5-HT but after all doses of ranitidine a decrease of the turnover was observed. The blockade of histamine H2 receptors with ranitidine did not completely abolish the effects of histamine on the 5-HT system, in the parts of the rat digestive system studied which suggests also an indirect activity of other receptors in presented observations. In the rat brain, an acceleration of the turnover of 5-HT after both doses of histamine was found. However, ranitidine only reduced the rate of 5-HT turnover at the lowest dose. In animals treated with ranitidine (15 mg/kg i.p.) for three days, histamine did not produce any change in the turnover of 5-HT in rat brain. These experiments show, that in the alimentary tract a relationship exists between histaminergic and serotoninergic systems.

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Arch Int Pharmacodyn Ther. 1985 Mar;274(1):166-76.
The effect of ranitidine on exocrine pancreatic secretion in the rat.

Chariot J, Roze C, Scarpignato C.

The effect of the H2-receptor antagonist ranitidine on pancreatic exocrine secretion was studied in the rat. In anaesthetized animals with acute fistulas pancreatic secretion was induced by central (2-deoxy-D-glucose, 2-DG) or peripheral (acetylcholine) cholinergic stimulants and by cholecystokinin and secretin. In some experiments cimetidine was used as a reference compound. Ranitidine (20 mg X kg-1 intraperitoneally) did not change neither basal secretion nor the response to the combined hormonal stimulation. On the contrary, it significantly increased 2-DG and acetylcholine-stimulated secretion, whereas cimetidine (100 mg X kg-1 intraperitoneally) inhibited the pancreatic response to 2-DG. The different behaviour of the two H2-antagonists suggests that the effect of ranitidine is independent of the H2-receptor blockade and most probably connected with the cholinergic-like action of the drug.

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Int J Clin Pharmacol Res. 1985;5(2):133-5.
Comparison between ranitidine and cimetidine in the short-term treatment of duodenal ulcer.

Capria A, Bresci G, Rindi G, Geloni M, Corsini G.

Two groups of 46 and 49 patients each with endoscopically proved duodenal ulcer and not previously treated, received ranitidine (150 mg X 2 daily) and cimetidine (1 g/day) respectively for eight weeks. The disappearance of the ulcer was observed endoscopically in 78% of both the first and second groups of patients. Of the ten patients non-responders to ranitidine, six were treated again for eight weeks with ranitidine and four with cimetidine for eight weeks; all of them recovered completely apart from one of the cimetidine treated patients. Of the 11 patients non-responders to cimetidine, seven were retreated with cimetidine and 4 with ranitidine for a further eight weeks and all of them obtained a complete recovery except for one of the cimetidine treated patients. No relevant side-effects were observed with either drug. In conclusion cimetidine and ranitidine showed a comparable therapeutic value.

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J Pediatr. 1985 Aug;107(2):301-6.
Pharmacokinetic determination of ranitidine pharmacodynamics in pediatric ulcer disease.

Blumer JL, Rothstein FC, Kaplan BS, Yamashita TS, Eshelman FN, Myers CM, Reed MD.

The pharmacokinetics and pharmacodynamics of ranitidine were evaluated during three methods of administration in 12 children ranging in age from 3.5 to 16 years with documented gastric or duodenal ulcer disease. First, a continuous intravenous infusion of ranitidine was administered to determine the serum concentration necessary to suppress gastric acid secretion by at least 90%. From these data a therapeutic dose of ranitidine was calculated and administered on separate days via the intravenous bolus and oral routes. Half-life, volume of distribution, and clearance values for ranitidine were the same after intravenous bolus and oral doses (1.8 vs 2.0 hours, 2.3 vs 2.5 L/kg, and 794.7 vs 788.0 ml/min/1.73 m2, respectively). The bioavailability of ranitidine given orally averaged 48%. Serum ranitidine concentrations necessary to inhibit gastric acid secretion by at least 90% ranged between 40 and 60 ng/ml for all children studied. No adverse clinical or biochemical effects were observed in any child during the 6 weeks of orally administered treatment. Endoscopic reevaluation after 6 weeks indicated complete healing of initial ulcers.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=4020560&dopt=Abstract ranitidine