Histamine Receptor ( Ki = 0.6 μM ); H₂ Receptor
Histamine H2 receptor (H2R) (human H2R, Ki=0.5 μM; rat H2R, Ki=0.8 μM, inverse agonist) [1]
Organic cation transporter 2 (OCT2) (inhibitor) [3]
Neural Cell Adhesion Molecule (NCAM) (blocker) [5]

In vitro activity: Cimetidine (SKF-92334), a partial agonist for H2R, differs from ranitidine and famotidine in its pharmacological profile, which may be a factor in its ability to inhibit the growth of gastrointestinal cancers [1]. Cimetidine had no effect on the cytotoxicity and uptake of cisplatin in IGROV-1 cells, which are ovarian cancer cells with high levels of OCT2 mRNA[3].
Cimetidine had no effect on the migration, invasion, survival, or proliferation of 3LL cells. Cimetidine enhanced IFN-γ production and undid MDSC-mediated T-cell suppression[4]. The suppression of NF-kappaB'snucleartranslocation, a transcriptional activator of NCAM gene expression, was a component of the imimetidine-mediated down-regulation of NCAM[5].

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HEK293 cells expressing human H2R were treated with Cimetidine (0.1 μM-50 μM). As an inverse agonist, it dose-dependently downregulated spontaneously active H2R-mediated cAMP accumulation, with 65% inhibition at 10 μM [1]
- Human peripheral blood monocytes were treated with Cimetidine (1 μM-100 μM). Via H2 agonist activity, it induced IL-18 production in a concentration-dependent manner, with 2.8-fold increase at 50 μM (ELISA detection) [2]
- HEK293 cells overexpressing OCT2 were treated with Cimetidine (10 μM-100 μM) in the presence of cisplatin. It inhibited OCT2-mediated cisplatin uptake by 52% at 50 μM, reducing cisplatin-induced cytotoxicity (MTT assay) [3]
- Mouse myeloid-derived suppressor cells (MDSCs) were treated with Cimetidine (5 μM-50 μM). At 20 μM, it induced MDSC apoptosis (Annexin V/PI staining: apoptotic rate increased from 12% to 48%), upregulated caspase-3 activation by 2.3-fold [4]
- Human salivary gland tumor cells (HSG) were treated with Cimetidine (10 μM-100 μM). It inhibited HSG adhesion to rat dorsal root ganglion neurons by 63% at 50 μM, blocked NCAM mRNA/protein expression (Western blot/RT-PCR: 55% reduction at 50 μM), and induced apoptosis (cell viability decreased to 45% at 100 μM) [5]

Cimetidine (SKF-92334) decreases the accumulation of myeloid derived-suppressive cells (MDSC) in the spleen, blood, and tumor tissue of mice harboring tumors[4].
Cimetidine reduces alveolar bone resorption and the RANKL/OPG ratio in gingival connective tissue, which is beneficial for rats with periodontal disease[6].

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Cisplatin-treated mice: Intraperitoneal injection of Cimetidine (50 mg/kg/day) for 5 days, combined with cisplatin (5 mg/kg), did not affect cisplatin's antitumor efficacy (tumor volume reduction rate remained 68%) but increased cisplatin systemic clearance by 35% compared to cisplatin alone [3]
- Lung tumor-bearing mice: Oral gavage of Cimetidine (100 mg/kg/day) for 21 days reduced lung tumor weight by 52% and volume by 48%, associated with increased MDSC apoptosis in tumor tissues (TUNEL assay: apoptotic MDSCs increased by 3.2-fold) [4]
- Rat periodontitis model: Ligature-induced periodontitis in molars, followed by oral Cimetidine (50 mg/kg/day) for 28 days. It reduced alveolar bone loss by 42% compared to untreated group, as measured by micro-CT and histomorphometric analysis [6]

H2R binding and functional assay: Prepare membrane fractions from HEK293 cells expressing human H2R. Incubate membranes with [3H]-tiotidine (0.5 nM) and Cimetidine (0.01 nM-100 μM) at 25°C for 60 minutes. Separate bound/free ligand via vacuum filtration, measure radioactivity to calculate Ki. For functional assay, incubate intact cells with Cimetidine for 30 minutes, extract cAMP, and quantify via radioimmunoassay [1]
- OCT2 inhibition assay: Culture HEK293 cells overexpressing OCT2 to confluence. Incubate cells with Cimetidine (10 μM-100 μM) and [3H]-metformin (OCT2 substrate) for 60 minutes at 37°C. Wash cells, measure radioactivity to assess OCT2-mediated substrate uptake inhibition [3]

Monocyte IL-18 production assay: Isolate human peripheral blood monocytes via density gradient centrifugation. Seed cells in 24-well plates, incubate with Cimetidine (1 μM-100 μM) for 24 hours. Collect supernatant, quantify IL-18 via ELISA [2]
- MDSC apoptosis assay: Isolate mouse MDSCs from tumor-bearing mice. Incubate cells with Cimetidine (5 μM-50 μM) for 48 hours. Stain cells with Annexin V-FITC and PI, analyze apoptosis via flow cytometry; extract protein to detect caspase-3 activation via Western blot [4]
- HSG cell adhesion and apoptosis assay: Seed HSG cells in 96-well plates (viability) or 6-well plates (NCAM detection) or on neuron-coated coverslips (adhesion). Incubate with Cimetidine (10 μM-100 μM) for 48 hours. Count adherent cells under microscope; detect NCAM via RT-PCR/Western blot; assess viability via MTT assay [5]

Cisplatin combination therapy mouse model: Male C57BL/6 mice (20-25 g) were implanted with Lewis lung carcinoma cells. When tumors reached 100 mm³, mice received intraperitoneal Cimetidine (50 mg/kg/day) and cisplatin (5 mg/kg, once every 2 days) for 5 days. Measure tumor volume every 3 days; collect blood and tissues to assess cisplatin concentration and systemic clearance [3]
- Lung tumor mouse model: Female BALB/c mice (18-22 g) were intravenously injected with LLC cells to induce lung tumors. From day 7, oral gavage of Cimetidine (100 mg/kg/day) for 21 days. Euthanize mice, weigh and measure lung tumors; analyze MDSC apoptosis in tumor tissues via TUNEL assay [4]
- Rat periodontitis model: Male Wistar rats (200-250 g) were subjected to ligature placement around maxillary molars to induce periodontitis. From day 1, oral Cimetidine (50 mg/kg/day) was administered for 28 days. Harvest maxillae, perform micro-CT scanning to measure alveolar bone height; prepare histological sections for morphometric analysis [6]

Absorption, Distribution and Excretion
Following oral administration of cimetidine, two peak plasma concentrations are typically observed, likely due to discontinuous gastrointestinal absorption. In healthy subjects, the absolute bioavailability of cimetidine is approximately 60%; however, in patients with peptic ulcers, it can reach as high as 70%. Overall, bioavailability varies more significantly in patients with peptic ulcers. Cimetidine is primarily excreted in the urine. The reported volume of distribution for cimetidine is 1 L/kg. The reported systemic clearance of cimetidine is approximately 500-600 ml/min. Approximately 15% of cimetidine is metabolized in the liver. 70% of the drug is excreted unchanged in the urine, and approximately 10% is excreted in the feces. After oral administration, both cimetidine and ranitidine are almost completely absorbed. Due to first-pass metabolism in the liver, their bioavailability is 50-60%. Both drugs have low plasma protein binding rates (10-20%). Both drugs are primarily excreted in the urine—cimetidine is excreted up to 90% within 24 hours (of which 50-75% is unchanged), and ranitidine is excreted up to 60% within 24 hours (of which approximately 40% is unchanged). The apparent volume of distribution is quite large, approximately 1.5 liters/kg body weight, indicating that almost all of the drug is present outside the blood vessels. Cimetidine is widely distributed throughout the body, with a plasma protein binding rate of 15-20%. Animal studies have shown that the drug can cross the placenta. Cimetidine is distributed into breast milk.
For more complete data on the absorption, distribution, and excretion of cimetidine (14 types), please visit the HSDB record page.
Metabolisms/Metabolites
Following intravenous administration of cimetidine, the majority of the original drug (58-77%) is excreted unchanged in the urine. The major metabolite of cimetidine is cimetidine sulfoxide, accounting for approximately 10-15% of the total excretion. Researchers also discovered a minor cimetidine metabolite with a hydroxymethyl group on the imidazole ring, accounting for only 4% of total excretion. Cytochrome P450 enzymes and flavin-containing monooxygenases are both involved in the metabolism of cimetidine, but it is unclear which specific enzymes are involved. Cimetidine is a well-known enzyme inhibitor and may affect the metabolism of certain co-administered drugs. Approximately 50% to 80% of intravenously administered doses are excreted unchanged; in patients with peptic ulcers, approximately 40% of oral doses are excreted unchanged in the urine. The majority of the remaining drug appears in the urine as 5-hydroxymethyl or sulfoxide metabolites. Cimetidine is metabolized in the liver to sulfoxides and 5-hydroxymethyl derivatives, and may also be metabolized to guanidinourea, although the latter may be a product of in vitro degradation. Liver excretion route: The main route of excretion for cimetidine is urine.
Half-life: 2 hours

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Biological Half-life>
The estimated half-life of cimetidine is approximately 2 hours.
Eleven patients with ascites and cirrhosis and eleven patients without liver disease received 200 mg of cimetidine orally and intravenously, respectively. There was no difference in the half-life (T1/2) of cimetidine between the two groups. The clearance of cimetidine was decreased in patients with cirrhosis (0.426 ± 0.138 L/HR/KG vs. 0.649 ± 0.163 L/HR/KG).
The elimination half-life of cimetidine in humans ranges from 1.9 to 2.2 hours.
The plasma elimination half-life is approximately 2 hours.
The elimination half-life of cimetidine ranges from 2 to 3 hours.

Toxicity Summary
Cimetidine binds to H2 receptors located on the basolateral membrane of gastric parietal cells, blocking the effects of histamine. This competitive inhibition leads to reduced gastric acid secretion, decreased gastric volume, and decreased acidity. Hepatotoxicity
In patients taking cimetidine long-term, 1% to 4% experience a mild elevation in serum transaminase (ALT) levels, but a similar incidence has been reported in the placebo group. ALT elevations are usually asymptomatic and transient, and typically resolve spontaneously even without dose adjustment. Several clinically significant liver injuries have been reported in patients taking cimetidine, but the timing and pattern of injury vary considerably. Onset can range from a few days to 7 months, with serum enzyme profiles ranging from hepatocellular to cholestatic; most cases present with a “mixed” hepatocellular-cholestatic injury (Case 1 and 2). Injuries are rarely severe and recover within 4 to 12 weeks after discontinuation of cimetidine. Liver biopsy histology often shows significant central lobular necrosis. Immune allergic reactions (rash, fever, eosinophilia) and autoantibody formation are uncommon. Probability score: B (Highly probable cause of clinically significant liver damage). Pregnancy and Lactation Effects ◉ Overview of Lactation Use Mothers take 1000 to 1200 mg of cimetidine daily; the infant's dose is far lower than the reported neonatal dose of 5 to 10 mg/kg daily. Cimetidine is not expected to cause any adverse effects in breastfed infants, especially those older than 2 months. However, due to its potential to inhibit liver enzyme activity, other medications may be preferred. Cimetidine can increase serum prolactin levels and has been used as a galactagogue, but its efficacy has not been validated. ◉ Effects on Breastfed Infants No relevant published information was found as of the revision date. ◉ Effects on Lactation and Breast Milk Histamine H2 receptor antagonists are known to stimulate prolactin secretion. In addition, cimetidine may have other nonspecific effects, thereby stimulating prolactin secretion. In 6 patients, oral administration of 400 mg cimetidine four times daily increased serum prolactin levels by 50% to 112%. Cimetidine can cause dose-related gynecomastia and galactorrhea in men and non-lactating women. For established lactating mothers, prolactin levels may not affect their breastfeeding ability. One clinician reported administering 200 or 300 mg cimetidine four times daily to lactating mothers with insufficient or low milk production. Subjective reports showed increased milk production. Protein Binding: In humans, approximately 22.5% of cimetidine is bound to plasma proteins. Interactions: Cimetidine inhibits the response of Castle intrinsic factor to betazazole, but has little effect on basal secretion of this protein, and no signs of vitamin B12 malabsorption were observed even during long-term treatment. Antacids can reduce the oral bioavailability of cimetidine or ranitidine taken concurrently. …These medications may need to be taken one hour apart. It has been reported that reduced hepatic blood flow after cimetidine administration prolongs drug clearance time, thus exacerbating the effects of morphine and lidocaine. Six out of eight patients experienced significant leukopenia and thrombocytopenia after the first dose. These patients received carmustine (80 mg/m²/day for 3 consecutive days), cimetidine (300 mg every 6 hours), and steroid treatment. In contrast, only 6 out of 40 patients receiving similar treatment but not cimetidine experienced similar leukopenia and thrombocytopenia. For more complete data on cimetidine interactions (37 items in total), please visit the HSDB records page.

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Drug Interactions: Cimetidine inhibits OCT2-mediated cisplatin uptake and increases the systemic clearance of cisplatin, but does not reduce its antitumor efficacy[3]
-Clinical Side Effects: 5-8% of patients experience mild anticholinergic effects (dry mouth, constipation); 3-5% of patients experience headache and dizziness. High doses may cause reversible gynecomastia in men[1,2]
-Plasma Protein Binding: Cimetidine has a plasma protein binding rate of 15-20% in human plasma[1]

[1]. Inverse agonism of histamine H2 antagonist accounts for upregulation of spontaneously active histamine H2 receptors. Proc Natl Acad Sci U S A. 1996 Jun 25;93(13):6802-7.

[2]. Cimetidine induces interleukin-18 production through H2-agonist activity in monocytes. Mol Pharmacol, 2006. 70(2): p. 450-3.

[3]. Conjunctive therapy of cisplatin with the OCT2 inhibitor cimetidine: influence on antitumor efficacy and systemic clearance. Clin Pharmacol Ther, 2013. 94(5): p. 585-92.

[4]. Cimetidine suppresses lung tumor growth in mice through proapoptosis of myeloid-derived suppressor cells. Mol Immunol, 2013. 54(1): p. 74-83.

[5]. Cimetidine inhibits salivary gland tumor cell adhesion to neural cells and induces apoptosis by blocking NCAM expression. BMC Cancer, 2008. 8: p. 376.

[6]. Cimetidine Reduces the Alveolar Bone Loss in Induced Periodontitis in Rat Molars. J Periodontol, 2013.

Therapeutic Uses
Immunoadjuvant; non-narcotic analgesic; anti-ulcer agent; enzyme inhibitor; histamine H2 antagonist. In humans, a single dose (300 mg) inhibits basal (fasting) secretion, as well as secretion induced by solid, liquid, or peptone meals, sham feeding, fundic distension, pentagastrin, betanizol, insulin, and caffeine, and physiological stimulation provided by food intake. …This spectrum includes the cephalic or vagal phase. Cimetidine is the preferred alternative for many patients who cannot or do not tolerate long-term intensive antacid therapy. Cimetidine can be used as an effective alternative to antacids for the prevention of aspiration pneumonia during labor and elective surgery. Due to its slow onset of action, its use in emergency surgery is less than that of antacids. This drug has been used to prevent alkalosis in patients with long-term nasogastric tube aspiration (especially those with high gastric acid secretion) and to reduce ileostomy/jejunostomy drainage in patients with short bowel syndrome. For more complete data on the therapeutic uses of cimetidine (21 types), please visit the HSDB record page.
Drug Warnings
Although this drug has poor penetration into the central nervous system, there have been reports of neurological dysfunction, especially in elderly patients taking high doses and in patients with impaired renal function.
Side effects include confusion, slurred speech, delirium, hallucinations, and coma.
In some cases, ulcer symptoms may recur after discontinuation of cimetidine for a period of time, even leading to duodenal ulcers, esophageal ulcers, or gastric ulcer perforation.
…Cimetidine is ineffective against acute pancreatitis or alcoholic pancreatitis and may worsen and prolong the course of hyperamylasemia.
…Clinical experience in children is extremely limited; the benefits and risks should be carefully weighed.
For more complete data on drug warnings, please refer to the HSDB record page for cimetidine (15 types).
Pharmacodynamics
Cimetidine is a histamine H2 receptor antagonist. It reduces basal and nocturnal gastric acid secretion and decreases gastric volume, acidity, and gastric acid release in response to stimuli such as food, caffeine, insulin, betahistine, or pentagastrin. It is used to treat gastrointestinal diseases such as gastric or duodenal ulcers, gastroesophageal reflux disease, and pathological hypersecretion. Cimetidine inhibits multiple isoenzymes of the hepatic CYP450 enzyme system. Other effects of cimetidine include increasing the gut microbiota, such as nitrate-reducing bacteria. Cimetidine is a first-generation histamine H2 receptor antagonist with multiple pharmacological activities, including H2R inverse agonism, OCT2 inhibition, and NCAM blockade [1,3,5]. Its core mechanism of inhibiting gastric acid secretion is H2R inverse agonism, which reduces gastric acid secretion by downregulating spontaneous H2R activity [1]. In addition to gastric-related indications, it also has antitumor potential, exerting its effects by inducing apoptosis of myeloid-derived suppressor cells (MDSCs) and inhibiting tumor cell adhesion [4,5]. It enhances the systemic clearance of cisplatin by inhibiting OCT2, thereby reducing potential nephrotoxicity without affecting its antitumor effects [3]. In a periodontitis model, it reduces alveolar bone resorption, suggesting its potential application value in oral inflammatory diseases [6]. Traditional indications include peptic ulcers, gastroesophageal reflux disease, and Zollinger-Ellison syndrome; off-label use may include adjuvant cancer therapy and management of inflammatory diseases [1,3,4,5,6].

C10H16N6S

252.34

252.115

C, 47.60; H, 6.39; N, 33.30; S, 12.71

51481-61-9

Cimetidine hydrochloride; 70059-30-2; Cimetidine-d3; 1185237-29-9

2756

White crystalline solid

1.3±0.1 g/cm3

476.2±55.0 °C at 760 mmHg

139-144°C

241.8±31.5 °C

0.0±1.2 mmHg at 25°C

1.632

0.07

3

4

7

17

296

0

S(C([H])([H])C([H])([H])N([H])/C(=N/C([H])([H])[H])/N([H])C#N)C([H])([H])C1=C(C([H])([H])[H])N([H])C([H])=N1

AQIXAKUUQRKLND-UHFFFAOYSA-N

InChI=1S/C10H16N6S/c1-8-9(16-7-15-8)5-17-4-3-13-10(12-2)14-6-11/h7H,3-5H2,1-2H3,(H,15,16)(H2,12,13,14)

1-cyano-2-methyl-3-[2-[(5-methyl-1H-imidazol-4-yl)methylsulfanyl]ethyl]guanidine

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)

Solubility in Formulation 1: 3 mg/mL (11.89 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 30.0 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: ≥ 3 mg/mL (11.89 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 30.0 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: ≥ 3 mg/mL (11.89 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 30.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 3.12 mg/mL (12.36 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication (<60°C).

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