Histamine H2 receptor

In vitro activity: Ranitidine increases the susceptibility of hepatocytes to death from cytotoxic products produced by activated neutrophils; this is not the case with metronidazole. [1] When lipopolysaccharide is used to stimulate monocytes in vitro, ranitidine prevents the production of tumor necrosis factor-alpha (TNF-alpha). Ranitidine [2] raises the relative concentration of morphine-6-glucuronide to morphine-3-glucuronide in isolated guinea pig hepatocytes and dose-dependently lowers the Kel of morphine with a maximum effect of 50%. The morphine-3-glucuronide/morphine-6-glucuronide ratio is progressively reduced by ranitidine by up to 21%.[3]

Ranitidine causes liver damage, as shown by elevated serum levels of gamma-glutamyl transferase, aspartate aminotransferase, and alanine aminotransferase in rats administered ranitidine for six hours.[1] Ranitidine inhibits the cytokine-induced neutrophil chemoattractant, the hepatic accumulation of neutrophils, and the increase in hepatic tissue levels of TNF-alpha caused by hepatic ischemia/reperfusion in rats.[2] In rats treated with LPS and RAN, anticoagulants lessen liver damage, while ranitidine cotreatment increases LPS-induced coagulation before liver injury. Rats given ranitidine or LPS develop fibrin clots in their liver sinusoids and are less likely to experience hepatocellular injury due to the prevention of fibrin deposition. In rats, ranitidine cotreatment amplifies the TNF rise brought on by LPS before hepatocellular damage manifests.[4]

The influence of ranitidine on morphine metabolism, with special emphasise on the ratio between morphine-3-glucuronide and morphine-6-glucuronide was studied in isolated guinea pig hepatocytes. Ranitidine reduced the Kel of morphine dose-dependently with a maximum effect of 50%, and increased the relative concentration of morphine-6-glucuronide to morphine-3-glucuronide. These effects could be due to a direct or indirect effect on the conjugation enzymes involved, or an effect on the transport of morphine or glucuronides across cell membranes. The latter explanation was rejected on the basis of the observation that the ratios between intra- and extracellular concentrations of morphine, morphine-3-glucuronide and morphine-6-glucuronide were not influenced by ranitidine. Increasing concentrations of ranitidine gradually decreased the morphine-3-glucuronide/morphine-6-glucuronide ratio by up to 21%. This could stem from interference of energy or co-substrate supply, or through direct effects on the different UDPGTases involved. The observation that the present effect on morphine glucuronidation was the opposite of that observed when administering a known co-substrate (UDPGA) depletor, indicated that in all probability the effect of ranitidine was a direct inhibition on the uridine 5'-diphosphate glucuronyltransferases involved, with a more pronounced effect for the isoenzymes responsible for the 3'-glucuronidation. [3]

Drug idiosyncrasy is an adverse event of unknown etiology that occurs in a small fraction of people taking a drug. Some idiosyncratic drug reactions may occur from episodic decreases in the threshold for drug hepatotoxicity. Previous studies in rats have shown that modest underlying inflammation triggered by bacterial lipopolysaccharide (LPS) can decrease the threshold for xenobiotic hepatotoxicity. The histamine-2 (H2)-receptor antagonist ranitidine (RAN) causes idiosyncratic reactions in people, with liver as a usual target. Researchers tested the hypothesis that RAN could be rendered hepatotoxic in animals undergoing a modest inflammatory response. [1]
Male rats were treated with a nonhepatotoxic dose of LPS (44 x 10(6) endotoxin units/kg i.v.) or its vehicle and then 2 h later with a nonhepatotoxic dose of RAN (30 mg/kg i.v.) or its vehicle. Liver injury was evident only in animals treated with both RAN and LPS as estimated by increases in serum alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyl transferase activities within 6 h after RAN administration. LPS/RAN cotreatment resulted in midzonal liver lesions characterized by acute necrosuppurative hepatitis. Famotidine (FAM) is an H2-antagonist for which the propensity for idiosyncratic reactions is far less than RAN. Rats given LPS and FAM at a dose pharmacologically equipotent to that of RAN did not develop liver injury. In vitro, RAN sensitized hepatocytes to killing by cytotoxic products from activated neutrophils, whereas FAM lacked this ability. The results indicate that a response resembling human RAN idiosyncrasy can be reproduced in animals by RAN exposure during modest inflammation.[1]

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Researchers previously reported that ranitidine, an H(2) receptor antagonist, inhibited neutrophil activation in vitro and in vivo, contributing to reduce stress-induced gastric mucosal injury in rats. In this study, Researchers examined whether ranitidine would reduce ischemia/reperfusion-induced liver injury, in which activated neutrophils are critically involved, in rats. Researchers also examined the effect of famotidine, another H(2) receptor antagonist, on leukocyte activation in vitro and after ischemia/reperfusion-induced liver injury in rats to know whether inhibition of neutrophil activation by ranitidine might be dependent on its blockade of H(2) receptors. Ranitidine inhibited the activation of neutrophils in vitro as reported previously, whereas famotidine significantly enhanced it. Ranitidine inhibited the production of tumor necrosis factor-alpha (TNF-alpha) in monocytes stimulated with lipopolysaccharide in vitro, whereas famotidine did not. Although hepatic ischemia/reperfusion-induced increases in hepatic tissue levels of TNF-alpha, cytokine-induced neutrophil chemoattractant, and hepatic accumulation of neutrophils were inhibited by intravenously administered 30 mg/kg ranitidine, these increases were significantly enhanced by 5 mg/kg i.v. famotidine. The decreases in both hepatic tissue blood flow and bile secretion and the increases in serum levels of transaminases seen after reperfusion were significantly inhibited by ranitidine, whereas these changes were more marked in animals given famotidine than in controls. These observations strongly suggested that ranitidine could reduce ischemia/reperfusion-induced liver injury by inhibiting neutrophil activation directly, or indirectly by inhibiting the production of TNF-alpha, which is a potent activator of neutrophils. Furthermore, the therapeutic efficacy of ranitidine might not be explained solely by its blockade of H(2) receptor.[2]

Metabolism / Metabolites
Ranitidine has known human metabolites that include Desmethylranitidine.

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Although interpatient variability exists, the dose of ranitidine in breastmilk is less than the dose used in newborn infants. However, the finding that ranitidine spontaneously breaks down to a cancer-causing chemical caused its removal from the market in the US and other countries. Other drugs are recommended.
◉ Effects in Breastfed Infants
One 54-day-old breastfed infant had no observable adverse effects after maternal ingestion of ranitidine 150 mg every 12 hours for 2 days.
◉ Effects on Lactation and Breastmilk
Histamine H2-receptor blockade is known to stimulate prolactin secretion. Ranitidine in intravenous doses over 100 mg or during long-term oral use have increased serum prolactin in some studies, and rare cases of gynecomastia have been reported. The prolactin level in a mother with established lactation may not affect her ability to breastfeed.

[1]. J Pharmacol Exp Ther. 2003 Oct;307(1):9-16.

[2]. J Pharmacol Exp Ther. 2002 Jun;301(3):1157-65.

[3]. Pharmacol Toxicol. 1998 Jun;82(6):272-9.

[4]. Toxicol Sci. 2007 Nov;100(1):267-80.

[5]. Neuropharmacology. 1998 Aug;37(8):1019-32.

Ranitidine is a member of the class of furans used to treat peptic ulcer disease (PUD) and gastroesophageal reflux disease. It has a role as an anti-ulcer drug, a H2-receptor antagonist, an environmental contaminant, a xenobiotic and a drug allergen. It is a member of furans, a tertiary amino compound, a C-nitro compound and an organic sulfide.
Ranitidine is a member of the class of histamine H2-receptor antagonists with antacid activity. Ranitidine is a competitive and reversible inhibitor of the action of histamine, released by enterochromaffin-like (ECL) cells, at the histamine H2-receptors on parietal cells in the stomach, thereby inhibiting the normal and meal-stimulated secretion of stomach acid. In addition, other substances that promote acid secretion have a reduced effect on parietal cells when the H2 receptors are blocked.
Ranitidine Hydrochloride is a member of the class of histamine H2-receptor antagonists with antacid activity. Ranitidine is a competitive and reversible inhibitor of the action of histamine, released by enterochromaffin-like (ECL) cells, at the histamine H2-receptors on parietal cells in the stomach, thereby inhibiting the normal and meal-stimulated secretion of stomach acid. In addition, other substances that promote acid secretion have a reduced effect on parietal cells when the H2 receptors are blocked.
A non-imidazole blocker of those histamine receptors that mediate gastric secretion (H2 receptors). It is used to treat gastrointestinal ulcers.
See also: Ranitidine (annotation moved to).

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Exposure to a nontoxic dose of bacterial lipopolysaccharide (LPS) increases the hepatotoxicity of the histamine-2 (H2) receptor antagonist, ranitidine (RAN). Because some of the pathophysiologic effects associated with LPS are mediated through the expression and release of inflammatory mediators such as tumor necrosis factor alpha (TNF), this study was designed to gain insights into the role of TNF in LPS/RAN hepatotoxicity. To determine whether RAN affects LPS-induced TNF release at a time near the onset of liver injury, male Sprague-Dawley rats were treated with 2.5 x 10(6) endotoxin units (EU)/kg LPS or its saline vehicle (iv) and 2 h later with either 30 mg/kg RAN or sterile phosphate-buffered saline vehicle (iv). LPS administration caused an increase in circulating TNF concentration. RAN cotreatment enhanced the LPS-induced TNF increase before the onset of hepatocellular injury, an effect that was not produced by famotidine, a H2-receptor antagonist without idiosyncrasy liability. Similar effects were observed for serum interleukin (IL)-1beta, IL-6, and IL-10. To determine if TNF plays a causal role in LPS/RAN-induced hepatotoxicity, rats were given either pentoxifylline (PTX; 100 mg/kg, iv) to inhibit the synthesis of TNF or etanercept (Etan; 8 mg/kg, sc) to impede the ability of TNF to reach cellular receptors, and then they were treated with LPS and RAN. Hepatocellular injury, the release of inflammatory mediators, hepatic neutrophil (PMN) accumulation, and biomarkers of coagulation and fibrinolysis were assessed. Pretreatment with either PTX or Etan resulted in the attenuation of liver injury and diminished circulating concentrations of TNF, IL-1beta, IL-6, macrophage inflammatory protein-2, and coagulation/fibrinolysis biomarkers in LPS/RAN-cotreated animals. Neither PTX nor Etan pretreatments altered hepatic PMN accumulation. These results suggest that TNF contributes to LPS/RAN-induced liver injury by enhancing inflammatory cytokine production and hemostasis.[4]

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This study examined the effects of the H1-antagonist chlorpheniramine and the H2-antagonist ranitidine on reinforcement and anxiety-parameters following unilateral injection into the vicinity of the nucleus basalis magnocellularis (NBM). In Experiment 1, rats with chronically implanted cannulae were injected with chlorpheniramine or ranitidine (each at doses of 0.1, 1, 10 and 20 microg) and were placed into one of four restricted quadrants of a circular open field (closed corral) for a single conditioning trial. During the test for conditioned corral preference, when provided a choice between the four quadrants, only those rats injected with 10 or 20 microg chlorpheniramine spent more time in the treatment corral, indicative of a positively reinforcing action. None of the other doses of chlorpheniramine or of the H2-antagonist influenced rats' preference behavior. In Experiment 2, the elevated plus-maze (EPM) was used to gauge possible anxiolytic or anxiogenic effects of intra-basalis injection of chlorpheniramine or ranitidine (each at doses of 0.1, 1, 10 and 20 microg). A single injection of chlorpheniramine at 0.1 or 20 microg as well as ranitidine at 20 microg was found to exert anxiolytic-like effects in the EPM. Both compounds elevated the time spent on the open arms and increased scanning over the edge of an open arm. None of the other doses of the H1- and H2-antagonist influenced rats' behavior in the EPM. In sum, these findings show that H1- and H2-receptor antagonists differentially modulate reinforcement and fear-related processes in the NBM and thus, provide the first evidence for a behavioral relevance for the histaminergic innervation of this brain site.[5]

C13H22N4O3S.HCL

350.87

314.141

C, 49.66; H, 7.05; N, 17.82; O, 15.27; S, 10.20

66357-35-5

Ranitidine hydrochloride;66357-59-3

3001055

Off-white to light brown solid at room temperature

1.2±0.1 g/cm3

437.1±45.0 °C at 760 mmHg

69-70°C

218.2±28.7 °C

0.0±1.0 mmHg at 25°C

1.559

1.23

2

7

9

21

347

0

CNC(=C[N+](=O)[O-])NCCSCC1=CC=C(CN(C)C)O1

VMXUWOKSQNHOCA-UKTHLTGXSA-N

InChI=1S/C13H22N4O3S/c1-14-13(9-17(18)19)15-6-7-21-10-12-5-4-11(20-12)8-16(2)3/h4-5,9,14-15H,6-8,10H2,1-3H3/b13-9+

(E)-1-N'-[2-[[5-[(dimethylamino)methyl]furan-2-yl]methylsulfanyl]ethyl]-1-N-methyl-2-nitroethene-1,1-diamine

ranitidine; 66357-35-5; Ranitidine Base; ranitidine hydrochloride; Raticina; Coralen; Gastrial; Quantor;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)