Histamine H2 receptor
Histamine H2 receptor (H2R) (human H2R, Ki=0.12 μM; rat H2R, Ki=0.34 μM) [1]
Histamine H2 receptor (H2R) [2,5]

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]

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Isolated canine parietal cells were stimulated with histamine (10 μM) to induce acid secretion. Ranitidine HCl (0.01 μM-10 μM) dose-dependently inhibited acid secretion, with an IC50 of 0.23 μM, confirming competitive H2R antagonism [1]
- Cultured rat gastric mucosal cells were treated with Ranitidine HCl (1 μM-50 μM) for 24 hours. The drug had no significant effect on cell viability but inhibited histamine-induced cAMP accumulation by 65% at 10 μM [2]
- Rat brain synaptosomal preparations were used to evaluate neurotransmitter release. Ranitidine HCl (10 μM-100 μM) did not affect KCl-induced glutamate or GABA release, indicating no interaction with central neurotransmitter systems [5]
- Human hepatoma HepG2 cells were treated with Ranitidine HCl (50 μM-500 μM) for 48 hours. No significant cytotoxicity was observed, with cell viability maintained above 90% even at 500 μM [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]

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Rat pylorus-ligated model: Oral administration of Ranitidine HCl (5 mg/kg, 10 mg/kg, 20 mg/kg) 1 hour before pylorus ligation dose-dependently reduced gastric acid secretion. The 20 mg/kg dose inhibited acid output by 78% and reduced gastric juice volume by 42% compared to vehicle [2]
- Rat indomethacin-induced gastric ulcer model: Intraperitoneal injection of Ranitidine HCl (10 mg/kg/day) for 3 days reduced ulcer index by 62%, promoted mucosal healing by increasing gastric mucus secretion [2]
- Normotensive rats: Intravenous administration of Ranitidine HCl (1 mg/kg-10 mg/kg) did not cause significant changes in systolic blood pressure, diastolic blood pressure, or heart rate [1]
- Acute toxicity study in mice: Single oral doses of Ranitidine HCl up to 5000 mg/kg did not induce mortality or severe clinical signs (e.g., ataxia, convulsions) [3]

H2R binding assay: Prepare membrane fractions from human embryonic kidney (HEK293) cells expressing human H2R or rat gastric mucosa. Incubate membranes with [3H]-tiotidine (0.5 nM) and various concentrations of Ranitidine HCl (0.01 nM-10 μM) at 37°C for 60 minutes. Separate bound and free ligand by vacuum filtration through glass fiber filters. Measure radioactivity with a liquid scintillation counter and calculate Ki values using the Cheng-Prusoff equation [1]

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]

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Parietal cell acid secretion assay: Isolate canine parietal cells via collagenase digestion and density gradient centrifugation. Suspend cells in culture medium and pre-treat with Ranitidine HCl (0.01 μM-10 μM) for 30 minutes. Stimulate with histamine (10 μM) for 2 hours, then measure acid secretion via [14C]-aminopyrine accumulation assay [1]
- Gastric mucosal cell cAMP assay: Seed rat gastric mucosal cells in 24-well plates and incubate for 24 hours. Pre-treat with Ranitidine HCl (1 μM-50 μM) for 1 hour, then stimulate with histamine (10 μM) for 30 minutes. Extract cAMP and quantify via radioimmunoassay [2]
- Hepatocyte cytotoxicity assay: Seed HepG2 cells in 96-well plates at 2×104 cells/well and incubate for 24 hours. Treat with Ranitidine HCl (50 μM-500 μM) for 48 hours. Add MTT reagent, incubate at 37°C for 4 hours, dissolve formazan crystals with DMSO, and measure absorbance at 570 nm [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. \n[1]
\nMale 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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\nResearchers 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]

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\nPylorus-ligated rat experiment: Male Sprague-Dawley rats (200-250 g) were fasted for 24 hours. Ranitidine HCl was dissolved in physiological saline and administered via oral gavage at 5 mg/kg, 10 mg/kg, 20 mg/kg. One hour later, the pylorus was ligated under anesthesia. Four hours post-ligation, rats were euthanized, gastric juice was collected to measure volume and acid output [2]
\n- Gastric ulcer model experiment: Male Wistar rats (180-220 g) were fasted for 24 hours. Indomethacin (20 mg/kg) was administered subcutaneously to induce gastric ulcers. Ranitidine HCl (10 mg/kg) was injected intraperitoneally once daily for 3 days. On day 4, rats were euthanized, and gastric mucosa was examined to calculate ulcer index [2]
\n- Acute toxicity experiment: Male and female ICR mice (18-22 g) were randomly divided into groups. Ranitidine HCl was dissolved in distilled water and administered via oral gavage at doses ranging from 1000 mg/kg to 5000 mg/kg. Mice were observed for 14 days for mortality, clinical signs, and body weight changes [3]
\n- Cardiovascular effect experiment: Normotensive male Sprague-Dawley rats (250-300 g) were anesthetized with urethane. A carotid artery catheter was implanted to measure blood pressure and heart rate. Ranitidine HCl (1 mg/kg-10 mg/kg) was administered via intravenous injection, and hemodynamic parameters were recorded for 60 minutes [1]

Metabolism/Metabolites
The known metabolites of ranitidine include demethylranitidine.

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Absorption: Oral bioavailability is 50-60%; peak plasma concentration (Cmax) is reached 1-2 hours after oral administration [1]
-Distribution: Volume of distribution (Vd) is 1.4 L/kg; it is widely distributed in tissues and hardly crosses the blood-brain barrier [1]
-Metabolism: It is mainly metabolized in the liver by N-demethylation to inactive metabolites [1]
-Excretion: 70% of the dose is excreted in the urine (30% as the original drug and 40% as metabolites), and 25% is excreted in the feces. In humans, the elimination half-life (t1/2) of ranitidine is 2.5-3 hours, and in rats it is 1.8 hours [1]
-Plasma protein binding: Ranitidine hydrochloride has a plasma protein binding rate of 15-20% in human plasma [1]

Effects During Pregnancy and Lactation
◉ Overview of Use During Lactation
Although there are individual differences, the dose of ranitidine in breast milk is lower than the dose for newborns. However, ranitidine has been withdrawn from the market in the United States and other countries due to its spontaneous breakdown into carcinogenic chemicals. Alternative medications are recommended.
◉ Effects on Breastfed Infants
No adverse reactions were observed in a 54-day-old breastfed infant after the mother received 150 mg of ranitidine every 12 hours for two consecutive days.
◉ Effects on Lactation and Breast Milk
Histamine H2 receptor antagonists are known to stimulate prolactin secretion. Some studies have shown that intravenous administration of ranitidine exceeding 100 mg or prolonged oral administration of ranitidine can lead to elevated serum prolactin levels, with rare reports of gynecomastia. For mothers who have established lactation, prolactin levels may not affect their ability to breastfeed.

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Acute toxicity: Oral LD50 in mice >5000 mg/kg; Intraperitoneal LD50 in rats was 3000 mg/kg, and oral LD50 was greater than 10000 mg/kg [3]
-Chronic toxicity: After 6 months of continuous oral administration of ranitidine hydrochloride (100 mg/kg/day) to rats, no significant changes were observed in liver and kidney function, hematological parameters or organ weight [4]
-Genetic toxicity: Neither the in vitro Ames test nor the in vivo micronucleus test showed that ranitidine hydrochloride had genotoxicity [3]
-Clinical side effects: 3-5% of patients experienced mild gastrointestinal discomfort (diarrhea, nausea); 2-4% of patients reported headache and dizziness. No significant cardiovascular or central nervous system toxicity was observed at therapeutic doses [1]

[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 belongs to the furan class of drugs and is used to treat peptic ulcers and gastroesophageal reflux disease. It has multiple effects, including anti-ulcer action, H2 receptor antagonism, action against environmental pollutants, exogenous substances, and drug allergens. It belongs to the furan class of compounds, tertiary amine compounds, C-nitro compounds, and organosulfur compounds. Ranitidine is a histamine H2 receptor antagonist with antacid activity. Ranitidine is a competitive and reversible inhibitor of histamine released from enterochromaffin-like cells (ECL cells) binding to histamine H2 receptors on gastric parietal cells, thereby inhibiting normal gastric acid secretion and gastric acid secretion induced by food intake. Furthermore, when H2 receptors are blocked, the effects of other substances that promote gastric acid secretion on parietal cells are also weakened. Ranitidine hydrochloride belongs to the class of histamine H2 receptor antagonists. Ranitidine is a competitive and reversible inhibitor of histamine released from enterochromaffin-like cells (ECL cells) that binds to histamine H2 receptors on gastric parietal cells, thereby inhibiting normal gastric acid secretion and food-induced gastric acid secretion. Furthermore, when H2 receptors are blocked, the effects of other substances that promote gastric acid secretion on parietal cells are also weakened. Ranitidine is a non-imidazole histamine receptor (H2 receptor) blocker that mediates gastric acid secretion. It is used to treat gastrointestinal ulcers. See also: Ranitidine (note moved to). Exposure to non-toxic doses of bacterial lipopolysaccharide (LPS) increases the hepatotoxicity of the histamine-2 (H2) receptor antagonist ranitidine (RAN). Since some pathophysiological effects associated with LPS are mediated through the expression and release of inflammatory mediators such as tumor necrosis factor-α (TNF), this study aimed to understand the role of TNF in LPS/RAN hepatotoxicity. To determine whether rapamycin (RAN) affects LPS-induced TNF release in the early stages of liver injury, we treated male Sprague-Dawley rats with 2.5 × 10⁶ endotoxin units (EU)/kg LPS or its saline solution (intravenous), followed by treatment with 30 mg/kg RAN or sterile phosphate-buffered saline (intravenous) 2 hours later. LPS administration led to an increase in circulating TNF concentrations. RAN combined with RAN treatment enhanced LPS-induced TNF elevation, and this elevation occurred before hepatocellular injury, while famotidine (a non-specific H2 receptor antagonist) did not have this effect. Similar changes were observed in serum interleukin (IL)-1β, IL-6, and IL-10. To determine whether TNF plays a causal role in LPS/RAN-induced hepatotoxicity, researchers administered pentoxifylline (PTX; 100 mg/kg, intravenously) to rats to inhibit TNF synthesis, or etanercept (Etan; 8 mg/kg, subcutaneously) to block TNF binding to cellular receptors, followed by LPS and RAN treatment. The researchers assessed hepatocellular injury, release of inflammatory mediators, hepatic neutrophil (PMN) aggregation, and biomarkers of coagulation and fibrinolysis. Results showed that pretreatment with PTX or Etan alleviated liver injury in animals treated with the combined LPS/RAN regimen and reduced circulating concentrations of TNF, IL-1β, IL-6, macrophage inflammatory protein-2, and coagulation/fibrinolysis biomarkers. However, neither PTX nor Etan pretreatment altered hepatic PMN aggregation. These results suggest that TNF promotes LPS/RAN-induced liver injury by enhancing the production of inflammatory cytokines and hemostatic effects. [4]

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This study investigated the effects of unilateral injection of the H1 receptor antagonist chlorpheniramine and the H2 receptor antagonist ranitidine on reinforcement and anxiety parameters near the basal ganglia large cell nucleus (NBM). In Experiment 1, rats with chronically implanted catheters were injected with chlorpheniramine or ranitidine (dose of 0.1, 1, 10, and 20 μg, respectively) and then placed in one of the four restricted quadrants of a circular open field (closed fence) for a single conditioned reflex training. In the conditioned fence preference test, only rats injected with 10 or 20 μg of chlorpheniramine stayed longer in the treated fence when choosing between the four quadrants, indicating that chlorpheniramine had a positive reinforcement effect. Other doses of chlorpheniramine or the H2 receptor antagonist did not affect the rats' preference behavior. In Experiment 2, we used the elevated cross maze (EPM) to assess the potential anxiolytic or anxiolytic effects of intrabasal membrane injection of chlorpheniramine or ranitidine (dose of 0.1, 1, 10, and 20 μg, respectively). The results showed that single injections of 0.1 or 20 μg of chlorpheniramine and 20 μg of ranitidine exhibited similar anxiolytic effects in the EPM. Both compounds increased the rats’ dwell time on the open arm and increased their scanning behavior at the edge of the open arm. Other doses of H1 and H2 receptor antagonists did not affect the rats’ behavior in the EPM. In summary, these results suggest that H1 and H2 receptor antagonists have different regulatory effects on reinforcement and fear-related processes in the basal forebrain (NBM), thus providing the first evidence of the correlation between histaminergic innervation of this brain region and behavior. [5]

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Ranitidine hydrochloride is a selective histamine H2 receptor antagonist primarily used to inhibit gastric acid secretion. [1,2]
Its mechanism of action involves competitive binding to H2 receptors on parietal cells, thereby blocking histamine-induced gastric acid secretion, cAMP accumulation and proton pump activation. [1,2]
Indications include peptic ulcers, gastroesophageal reflux disease (GERD), Zollinger-Ellison syndrome, and prevention of stress-induced gastric ulcers. [1]
It has no significant affinity for histamine H1 receptors, muscarinic receptors, or adrenergic receptors, and therefore its effect is minimal. Anticholinergic or sedative side effects [1,5]
Unlike first-generation H2 receptor antagonists, it has higher selectivity for H2 receptors and a longer duration of action (12 hours), so it can be administered twice daily. [2]

C13H23CLN4O3S

350.86

350.117

C, 44.50; H, 6.61; Cl, 10.10; N, 15.97; O, 13.68; S, 9.14

66357-59-3

Ranitidine-d6 hydrochloride; 1185238-09-8; Ranitidine; 66357-35-5; Ranitidine bismuth citrate; 128345-62-0; 66357-59-3 (HCl); 71130-06-8 (HCl)

3001055

Off-white to yellow solid powder

134°C (dec.)

3.566

2

7

9

21

347

0

S(C([H])([H])C([H])([H])N([H])/C(=C(\[H])/[N+](=O)[O-])/N([H])C([H])([H])[H])C([H])([H])C1=C([H])C([H])=C(C([H])([H])N(C([H])([H])[H])C([H])([H])[H])O1

GGWBHVILAJZWKJ-KJEVSKRMSA-N

InChI=1S/C13H22N4O3S.ClH/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;1H/b13-9+;

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

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

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

Solubility in Formulation 1: ≥ 2.08 mg/mL (5.93 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (5.93 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
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.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (5.93 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 110 mg/mL (313.52 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

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