An official website of the United States government

Cimetidine

PubChem CID
2756
Structure
Cimetidine_small.png
Cimetidine_3D_Structure.png
Cimetidine__Crystal_Structure.png
Molecular Formula
Synonyms
  • cimetidine
  • 51481-61-9
  • Tagamet
  • Ulcedin
  • Acinil
Molecular Weight
252.34 g/mol
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Dates
  • Create:
    2004-09-16
  • Modify:
    2025-01-18
Description
Cimetidine appears as white crystals with a slight sulfur-mercaptan odor. (NTP, 1992)
National Toxicology Program, Institute of Environmental Health Sciences, National Institutes of Health (NTP). 1992. National Toxicology Program Chemical Repository Database. Research Triangle Park, North Carolina.
Cimetidine is a member of the class of guanidines that consists of guanidine carrying a methyl substituent at position 1, a cyano group at position 2 and a 2-{[(5-methyl-1H-imidazol-4-yl)methyl]sulfanyl}ethyl group at position 3. It is a H2-receptor antagonist that inhibits the production of acid in stomach. It has a role as a H2-receptor antagonist, a P450 inhibitor, an anti-ulcer drug, an analgesic and an adjuvant. It is a member of guanidines, a member of imidazoles, an aliphatic sulfide and a nitrile.
A histamine congener, it competitively inhibits histamine binding to histamine H2 receptors. Cimetidine has a range of pharmacological actions. It inhibits gastric acid secretion, as well as pepsin and gastrins output. It also blocks the activity of cytochrome P-450 which might explain proposals for use in neoadjuvant therapy.

1 Structures

1.1 2D Structure

Chemical Structure Depiction
Cimetidine.png

1.2 3D Conformer

1.3 Crystal Structures

1 of 2
View All
CCDC Number
Crystal Structure Data
Crystal Structure Depiction
Crystal Structure Depiction

2 Names and Identifiers

2.1 Computed Descriptors

2.1.1 IUPAC Name

1-cyano-2-methyl-3-[2-[(5-methyl-1H-imidazol-4-yl)methylsulfanyl]ethyl]guanidine
Computed by Lexichem TK 2.7.0 (PubChem release 2021.10.14)

2.1.2 InChI

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)
Computed by InChI 1.0.6 (PubChem release 2021.10.14)

2.1.3 InChIKey

AQIXAKUUQRKLND-UHFFFAOYSA-N
Computed by InChI 1.0.6 (PubChem release 2021.10.14)

2.1.4 SMILES

CC1=C(N=CN1)CSCCNC(=NC)NC#N
Computed by OEChem 2.3.0 (PubChem release 2024.12.12)

2.2 Molecular Formula

C10H16N6S
Computed by PubChem 2.2 (PubChem release 2021.10.14)

2.3 Other Identifiers

2.3.1 CAS

51481-61-9

2.3.2 European Community (EC) Number

2.3.3 UNII

2.3.4 ChEBI ID

2.3.5 ChEMBL ID

2.3.6 DrugBank ID

2.3.7 DSSTox Substance ID

2.3.8 HMDB ID

2.3.9 KEGG ID

2.3.10 Metabolomics Workbench ID

2.3.11 NCI Thesaurus Code

2.3.12 Nikkaji Number

2.3.13 NSC Number

2.3.14 PharmGKB ID

2.3.15 Pharos Ligand ID

2.3.16 RXCUI

2.3.17 Wikidata

2.3.18 Wikipedia

2.4 Synonyms

2.4.1 MeSH Entry Terms

  • Altramet
  • Biomet
  • Biomet400
  • Cimetidine
  • Cimetidine HCl
  • Cimetidine Hydrochloride
  • Eureceptor
  • HCl, Cimetidine
  • Histodil
  • Hydrochloride, Cimetidine
  • N-Cyano-N'-methyl-N''-(2-(((5-methyl-1H-imidazol-4-yl)methyl)thio)ethyl)guanidine
  • SK and F 92334
  • SK and F-92334
  • SK and F92334
  • SKF 92334
  • SKF-92334
  • SKF92334
  • Tagamet

2.4.2 Depositor-Supplied Synonyms

3 Chemical and Physical Properties

3.1 Computed Properties

Property Name
Molecular Weight
Property Value
252.34 g/mol
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
XLogP3
Property Value
0.4
Reference
Computed by XLogP3 3.0 (PubChem release 2021.10.14)
Property Name
Hydrogen Bond Donor Count
Property Value
3
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Hydrogen Bond Acceptor Count
Property Value
4
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Rotatable Bond Count
Property Value
7
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Exact Mass
Property Value
252.11571571 Da
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
Monoisotopic Mass
Property Value
252.11571571 Da
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
Topological Polar Surface Area
Property Value
114 Ų
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Heavy Atom Count
Property Value
17
Reference
Computed by PubChem
Property Name
Formal Charge
Property Value
0
Reference
Computed by PubChem
Property Name
Complexity
Property Value
296
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Isotope Atom Count
Property Value
0
Reference
Computed by PubChem
Property Name
Defined Atom Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Undefined Atom Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Defined Bond Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Undefined Bond Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Covalently-Bonded Unit Count
Property Value
1
Reference
Computed by PubChem
Property Name
Compound Is Canonicalized
Property Value
Yes
Reference
Computed by PubChem (release 2021.10.14)

3.2 Experimental Properties

3.2.1 Physical Description

Cimetidine appears as white crystals with a slight sulfur-mercaptan odor. (NTP, 1992)
National Toxicology Program, Institute of Environmental Health Sciences, National Institutes of Health (NTP). 1992. National Toxicology Program Chemical Repository Database. Research Triangle Park, North Carolina.
Solid

3.2.2 Color / Form

Crystals
Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989., p. 354

3.2.3 Odor

Unpleasant odor
McEvoy, G.K. (ed.). AHFS Drug Information 90. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1990 (Plus Supplements 1990)., p. 1666

3.2.4 Taste

Bitter taste
Gerhartz, W. (exec ed.). Ullmann's Encyclopedia of Industrial Chemistry. 5th ed.Vol A1: Deerfield Beach, FL: VCH Publishers, 1985 to Present., p. VA3 322

3.2.5 Melting Point

284 to 290 °F (NTP, 1992)
National Toxicology Program, Institute of Environmental Health Sciences, National Institutes of Health (NTP). 1992. National Toxicology Program Chemical Repository Database. Research Triangle Park, North Carolina.
142 °C
PhysProp
141-143 °C
Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989., p. 354
142 °C

3.2.6 Solubility

5 mg/mL at 68 °F (NTP, 1992)
National Toxicology Program, Institute of Environmental Health Sciences, National Institutes of Health (NTP). 1992. National Toxicology Program Chemical Repository Database. Research Triangle Park, North Carolina.
9380 mg/L (at 25 °C)
MCFARLAND,JW ET AL. (2001)
IN WATER AT 37 °C: 1.14%; SOLUBILITY INCR BY DIL HYDROCHLORIC ACID
Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989., p. 354
Soluble in alcohol
McEvoy, G.K. (ed.). AHFS Drug Information 90. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1990 (Plus Supplements 1990)., p. 1666
8.16e-01 g/L

3.2.7 LogP

0.4
HANSCH,C ET AL. (1995)
log Kow= 0.40 (measured)
Hansch C, Leo AJ; Medchem Project Issue No. 26 Claremont, CA: Pomona College (1985)
1

3.2.8 LogS

-1.35
ADME Research, USCD

3.2.9 Caco2 Permeability

-5.89
ADME Research, USCD

3.2.10 Dissociation Constants

pKa
6.8
TOMLINSON,E & HAFKENSCHEID,TL (1986)
pKa= 6.8
McEvoy, G.K. (ed.). AHFS Drug Information 90. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1990 (Plus Supplements 1990)., p. 1666

3.2.11 Collision Cross Section

154.58 Ų [M+H]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

160.52 Ų [M+K]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

159.55 Ų [M+Na]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

Ross et al. JASMS 2022; 33; 1061-1072. DOI:10.1021/jasms.2c00111
156.5 Ų [M+H]+ [CCS Type: TW; Method: Major Mix IMS/Tof Calibration Kit (Waters)]
155.7 Ų [M+H]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

3.3 Chemical Classes

Other Uses -> Pharmaceuticals
Pharmaceutical

3.3.1 Drugs

Pharmaceuticals -> Antiulcer Drugs
S56 | UOATARGPHARMA | Target Pharmaceutical/Drug List from University of Athens | DOI:10.5281/zenodo.3248837
Pharmaceuticals
S10 | SWISSPHARMA | Pharmaceutical List with Consumption Data | DOI:10.5281/zenodo.2623484
Pharmaceuticals -> Listed in ZINC15
S55 | ZINC15PHARMA | Pharmaceuticals from ZINC15 | DOI:10.5281/zenodo.3247749
3.3.1.1 Human Drugs
Breast Feeding; Lactation; Milk, Human; Anti-Ulcer Agents; Histamine H2 Antagonists; Gastrointestinal Agents
Human drug -> Prescription; Over-the-counter; Discontinued; Active ingredient (CIMETIDINE)
Human drug -> Over-the-counter; Discontinued
Human drug -> Discontinued

4 Spectral Information

4.1 1D NMR Spectra

4.1.1 1H NMR Spectra

1 of 3
View All
Spectra ID
Instrument Type
JEOL
Frequency
400 MHz
Solvent
DMSO-d6
Shifts [ppm]:Intensity
2.59:149.00, 2.55:140.00, 2.14:1000.00, 2.57:189.00, 3.65:433.00, 3.33:43.00, 3.29:77.00, 2.71:601.00, 7.18:61.00, 3.34:68.00, 2.70:597.00, 3.30:142.00, 3.32:138.00
Thumbnail
Thumbnail
2 of 3
View All
Instrument Name
BRUKER AC-300
Source of Sample
Tokyo Kasei Kogyo Company, Ltd., Tokyo, Japan
Copyright
Copyright © 1991-2024 John Wiley & Sons, Inc. All Rights Reserved.
Thumbnail
Thumbnail

4.1.2 13C NMR Spectra

1 of 2
Source of Sample
Tokyo Kasei Kogyo Company, Ltd., Tokyo, Japan
Copyright
Copyright © 1980, 1981-2024 John Wiley & Sons, Inc. All Rights Reserved.
Thumbnail
Thumbnail
2 of 2
Copyright
Copyright © 2002-2024 Wiley-VCH Verlag GmbH & Co. KGaA. All Rights Reserved.
Thumbnail
Thumbnail

4.2 Mass Spectrometry

4.2.1 GC-MS

1 of 6
View All
NIST Number
237089
Library
Main library
Total Peaks
176
m/z Top Peak
95
m/z 2nd Highest
96
m/z 3rd Highest
126
Thumbnail
Thumbnail
2 of 6
View All
NIST Number
246448
Library
Replicate library
Total Peaks
113
m/z Top Peak
95
m/z 2nd Highest
96
m/z 3rd Highest
126
Thumbnail
Thumbnail

4.2.2 MS-MS

1 of 9
View All
Spectra ID
Ionization Mode
Positive
Top 5 Peaks

159.0697 100

117.048 63.98

95.0603 51.07

253.1228 13.93

172.0901 4.44

Thumbnail
Thumbnail
2 of 9
View All
Spectra ID
Ionization Mode
Positive
Top 5 Peaks

95.0603 100

159.0698 61.52

117.048 59.21

99.0664 19.88

103.0324 3.59

Thumbnail
Thumbnail

4.2.3 LC-MS

1 of 40
View All
Authors
Stravs M, Schymanski E, Singer H, Department of Environmental Chemistry, Eawag and Thomaidis N, University of Athens
Instrument
Q Exactive Plus Orbitrap Thermo Scientific
Instrument Type
LC-ESI-QFT
MS Level
MS2
Ionization Mode
POSITIVE
Ionization
ESI
Collision Energy
15 (nominal)
Fragmentation Mode
HCD
Column Name
XBridge C18 3.5um, 2.1x50mm, Waters
Retention Time
2.0 min
Precursor m/z
253.123
Precursor Adduct
[M+H]+
Top 5 Peaks

253.1227 999

159.0697 711

117.048 397

95.0602 142

211.1011 92

Thumbnail
Thumbnail
License
CC BY
2 of 40
View All
Authors
Stravs M, Schymanski E, Singer H, Department of Environmental Chemistry, Eawag and Thomaidis N, University of Athens
Instrument
Q Exactive Plus Orbitrap Thermo Scientific
Instrument Type
LC-ESI-QFT
MS Level
MS2
Ionization Mode
POSITIVE
Ionization
ESI
Collision Energy
30 (nominal)
Fragmentation Mode
HCD
Column Name
XBridge C18 3.5um, 2.1x50mm, Waters
Retention Time
2.0 min
Precursor m/z
253.123
Precursor Adduct
[M+H]+
Top 5 Peaks

159.0697 999

117.048 639

95.0603 510

253.1228 139

172.0901 44

Thumbnail
Thumbnail
License
CC BY

4.3 IR Spectra

4.3.1 FTIR Spectra

1 of 2
Technique
KBr WAFER
Source of Sample
Tokyo Kasei Kogyo Company, Ltd., Tokyo, Japan
Copyright
Copyright © 1980, 1981-2024 John Wiley & Sons, Inc. All Rights Reserved.
Thumbnail
Thumbnail
2 of 2
Technique
Mull
Source of Spectrum
Sigma-Aldrich Co. LLC.
Source of Sample
Aldrich
Catalog Number
285412
Copyright
Copyright © 2018-2024 Sigma-Aldrich Co. LLC. - Database Compilation Copyright © 2018-2024 John Wiley & Sons, Inc. All Rights Reserved.
Thumbnail
Thumbnail

4.3.2 ATR-IR Spectra

Instrument Name
Bio-Rad FTS
Technique
ATR-Neat (DuraSamplIR II)
Source of Spectrum
Forensic Spectral Research
Source of Sample
Alltech Associates, Inc., Grace Davison Discovery Sciences
Catalog Number
01426
Lot Number
539
Copyright
Copyright © 2009-2024 John Wiley & Sons, Inc. All Rights Reserved.
Thumbnail
Thumbnail

4.4 Raman Spectra

Technique
FT-Raman
Source of Spectrum
Forensic Spectral Research
Source of Sample
Alltech Associates, Inc., Grace Davison Discovery Sciences
Catalog Number
01426
Lot Number
539
Copyright
Copyright © 2012-2024 John Wiley & Sons, Inc. All Rights Reserved.
Thumbnail
Thumbnail

6 Chemical Vendors

7 Drug and Medication Information

7.1 Drug Indication

Cimetidine is indicated to reduce gastric acid secretion and to treat the following disease states: duodenal ulcers, non-malignant gastric ulcers, gastroesophageal reflux disease, and pathological hypersecretion associated with Zollinger-Ellison Syndrome, systemic mastocytosis, and multiple endocrine adenomas. It is indicated for prophylaxis of recurrent gastric or duodenal ulcers, as adjunctive therapy in the management of cystic fibrosis in children, and to treat NSAID induced lesions and gastrointestinal symptoms.

7.2 LiverTox Summary

Cimetidine is a histamine type 2 receptor antagonist (H2 blocker) which is widely used for treatment of acid-peptic disease and heartburn. Cimetidine has been linked to rare instances of clinically apparent acute liver injury.

7.3 Drug Classes

Breast Feeding; Lactation; Milk, Human; Anti-Ulcer Agents; Histamine H2 Antagonists; Gastrointestinal Agents
Antiulcer Agents

7.4 FDA Approved Drugs

7.5 FDA Orange Book

7.6 FDA National Drug Code Directory

7.7 Drug Labels

Drug and label
Active ingredient and drug

7.8 Clinical Trials

7.8.1 ClinicalTrials.gov

7.8.2 EU Clinical Trials Register

7.8.3 NIPH Clinical Trials Search of Japan

7.9 Therapeutic Uses

Adjuvants, Immunologic; Analgesics, Non-Narcotic; Anti-Ulcer Agents; Enzyme Inhibitors; Histamine H2 Antagonists
National Library of Medicine's Medical Subject Headings online file (MeSH, 1999)
IN MAN, A SINGLE DOSE (300 MG) WILL INHIBIT BASAL (FASTING) SECRETION AND ALSO SECRETION INDUCED BY SOLID, LIQ, OR PEPTONE MEALS, SHAM FEEDING, FUNDIC DISTENTION, PENTAGASTRIN, BETHANECHOL, INSULIN, AND CAFFEINE, AS WELL AS THE PHYSIOLOGICAL STIMULUS PROVIDED BY EATING. ... THIS SPECTRUM INCL THE CEPHALIC OR VAGAL PHASE.
Gilman, A. G., L. S. Goodman, and A. Gilman. (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 6th ed. New York: Macmillan Publishing Co., Inc. 1980., p. 631
CIMETIDINE IS THE PREFERRED ALTERNATIVE FOR MANY PATIENTS WHO CANNOT OR WILL NOT TOLERATE AN INTENSIVE, PROLONGED ANTACID REGIMEN.
American Medical Association, Council on Drugs. AMA Drug Evaluations Annual 1994. Chicago, IL: American Medical Association, 1994., p. 899
Cimetidine is a useful alternative to antacids in preventing aspiration pneumonitis during childbirth and elective surgical procedures. It is less useful than antacids during emergency surgery because of its slow onset of action. This drug had been given to prevent alkalosis in patients subjected to prolonged nasogastric aspiration, especially those secreting large amounts of acid, and to decrease ileostomy/jejunostomy output in the short bowel syndrome.
American Medical Association, Council on Drugs. AMA Drug Evaluations Annual 1994. Chicago, IL: American Medical Association, 1994., p. 899
For more Therapeutic Uses (Complete) data for CIMETIDINE (21 total), please visit the HSDB record page.

7.10 Drug Warnings

DESPITE POOR PENETRATION TO THE CNS, NEURAL DYSFUNCTION HAS BEEN ENCOUNTERED, PARTICULARLY WITH HIGH DOSES IN ELDERLY PATIENTS AND IN ASSOCIATION WITH IMPAIRED RENAL EXCRETION. THE EFFECTS INCL CONFUSION, SLURRED SPEECH, DELIRIUM, HALLUCINATIONS, AND COMA.
Gilman, A. G., L. S. Goodman, and A. Gilman. (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 6th ed. New York: Macmillan Publishing Co., Inc. 1980., p. 631
IN SOME INSTANCES, WITHDRAWAL OF CIMETIDINE AFTER A PERIOD OF TREATMENT HAS BEEN FOLLOWED BY RELAPSES IN THE SYMPTOMS OF ULCER AND EVEN BY PERFORATION OF DUODENAL, ESOPHAGEAL, OR GASTRIC ULCERS.
Gilman, A. G., L. S. Goodman, and A. Gilman. (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 6th ed. New York: Macmillan Publishing Co., Inc. 1980., p. 632
... CIMETIDINE IS INEFFECTIVE IN ACUTE OR ALCOHOLIC PANCREATITIS AND IT MAY ACTUALLY INCR AND PROLONG HYPERAMYLASEMIA.
American Medical Association, Council on Drugs. AMA Drug Evaluations Annual 1994. Chicago, IL: American Medical Association, 1994., p. 899
... CLIN EXPERIENCE IN CHILDREN IS EXTREMELY LIMITED, AND THE BENEFIT/RISK RATIO SHOULD BE CONSIDERED CAREFULLY.
American Medical Association. AMA Drug Evaluations Annual 1991. Chicago, IL: American Medical Association, 1991., p. 771
For more Drug Warnings (Complete) data for CIMETIDINE (15 total), please visit the HSDB record page.

7.11 Drug Tolerance

GRADUALLY DECR RESPONSIVENESS AFTER PROLONGED USE HAS BEEN REPORTED OCCASIONALLY.
American Medical Association, AMA Department of Drugs. AMA Drug Evaluations. 5th ed. Chicago: American Medical Association, 1983., p. 1266

8 Pharmacology and Biochemistry

8.1 Pharmacodynamics

Cimetidine is a histamine H2-receptor antagonist. It reduces basal and nocturnal gastric acid secretion and a reduction in gastric volume, acidity, and amount of gastric acid released in response to stimuli including food, caffeine, insulin, betazole, or pentagastrin. It is used to treat gastrointestinal disorders such as gastric or duodenal ulcer, gastroesophageal reflux disease, and pathological hypersecretory conditions. Cimetidine inhibits many of the isoenzymes of the hepatic CYP450 enzyme system. Other actions of Cimetidine include an increase in gastric bacterial flora such as nitrate-reducing organisms.

8.2 MeSH Pharmacological Classification

Cytochrome P-450 CYP1A2 Inhibitors
Drugs and compounds which inhibit or antagonize the biosynthesis or actions of CYTOCHROME P-450 CYP1A2. (See all compounds classified as Cytochrome P-450 CYP1A2 Inhibitors.)
Histamine H2 Antagonists
Drugs that selectively bind to but do not activate histamine H2 receptors, thereby blocking the actions of histamine. Their clinically most important action is the inhibition of acid secretion in the treatment of gastrointestinal ulcers. Smooth muscle may also be affected. Some drugs in this class have strong effects in the central nervous system, but these actions are not well understood. (See all compounds classified as Histamine H2 Antagonists.)
Anti-Ulcer Agents
Various agents with different action mechanisms used to treat or ameliorate PEPTIC ULCER or irritation of the gastrointestinal tract. This has included ANTIBIOTICS to treat HELICOBACTER INFECTIONS; HISTAMINE H2 ANTAGONISTS to reduce GASTRIC ACID secretion; and ANTACIDS for symptomatic relief. (See all compounds classified as Anti-Ulcer Agents.)

8.3 FDA Pharmacological Classification

1 of 2
FDA UNII
80061L1WGD
Active Moiety
CIMETIDINE
Pharmacological Classes
Mechanisms of Action [MoA] - Histamine H2 Receptor Antagonists
Pharmacological Classes
Established Pharmacologic Class [EPC] - Histamine-2 Receptor Antagonist
FDA Pharmacology Summary
Cimetidine is a Histamine-2 Receptor Antagonist. The mechanism of action of cimetidine is as a Histamine H2 Receptor Antagonist.
2 of 2
Non-Proprietary Name
CIMETIDINE
Pharmacological Classes
Histamine H2 Receptor Antagonists [MoA]; Histamine-2 Receptor Antagonist [EPC]

8.4 ATC Code

A - Alimentary tract and metabolism

A02 - Drugs for acid related disorders

A02B - Drugs for peptic ulcer and gastro-oesophageal reflux disease (gord)

A02BA - H2-receptor antagonists

A02BA01 - Cimetidine

8.5 Absorption, Distribution and Excretion

Absorption
Two peak plasma concentrations are often observed after oral administration of cimetidine, likely as a result of discontinuous absorption in the gastrointestinal tract. In healthy patients, the absolute bioavailability of cimetidine is approximately 60%; however, the bioavailability can be as high as 70% in patients with peptic ulcer disease. Overall, rates of bioavailability are much more variable in patients with peptic ulcer disease.
Route of Elimination
Cimetidine is excreted primarily in the urine.
Volume of Distribution
The volume of distribution of cimetidine is reported to be 1 L/kg.
Clearance
Cimetidine's reported systemic clearance value is approximately 500-600 ml/min.
About 15% of cimetidine is metabolized in the liver. Seventy percent is excreted unchanged in the urine, with fecal losses accounting for approximately 10%.
Ellenhorn, M.J. and D.G. Barceloux. Medical Toxicology - Diagnosis and Treatment of Human Poisoning. New York, NY: Elsevier Science Publishing Co., Inc. 1988., p. 434
Given orally, cimetidine and ranitidine are almost completely absorbed. Because of first-pass metabolism in the liver, the bioavailability is 50-60%. Both drugs are little bound to plasma proteins (10-20%).
Haddad, L.M., Clinical Management of Poisoning and Drug Overdose. 2nd ed. Philadelphia, PA: W.B. Saunders Co., 1990., p. 824
Both drugs are mainly excreted in urine - cimetidine up to 90% within 24 hr (50-75% unchanged) and ranitidine up to 60% within 24 hr (about 40% unchanged). The apparent volume of distribution is quite large, in the range of 1.5 l/kg bw, demonstrating that nearly all drug exists outside the intravascular space.
Haddad, L.M., Clinical Management of Poisoning and Drug Overdose. 2nd ed. Philadelphia, PA: W.B. Saunders Co., 1990., p. 824
Cimetidine is widely distributed throughout the body and is 15-20% bound to plasma proteins. Animal studies indicate that the drug crosses the placenta. Cimetidine is distributed into milk.
McEvoy G.K. (ed.). American Hospital Formulary Service-Drug Information 96. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 1996 (Plus Supplements)., p. 2140
For more Absorption, Distribution and Excretion (Complete) data for CIMETIDINE (14 total), please visit the HSDB record page.

8.6 Metabolism / Metabolites

After intravenous administration of cimetidine, the majority of the parent drug (58-77%) is eliminated unchanged in the urine. Cimetidine’s primary metabolite is cimetidine sulfoxide and represents an estimated 10-15% of total elimination. Researchers have also identified a minor cimetidine metabolite with a hydroxylated methyl group on the imidazole ring which represents only 4% of total elimination. Both cytochrome P450 enzymes and flavin-containing monooxygenases are implicated in the metabolism of cimetidine, although it is unclear which specific enzymes are involved. Cimetidine is a well known enzyme inhibitor and may impair the metabolism of certain co-administered medications.
About 50% to 80% of an intravenous dose is excreted as unchanged drug; 40% of an oral dose is excreted unchanged in the urine in patients with peptic ulcer disease. Most of the remainder of the drug appears in the urine as 5-hydroxymethyl or sulfoxide metabolites.
American Medical Association, Council on Drugs. AMA Drug Evaluations Annual 1994. Chicago, IL: American Medical Association, 1994., p. 900
Cimetidine is metabolized in the liver to sulfoxide and 5-hydroxymethyl derivatives, and possibly guanylurea, although this latter compound may result from in vitro degradation.
McEvoy G.K. (ed.). American Hospital Formulary Service-Drug Information 96. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 1996 (Plus Supplements)., p. 2140
Hepatic Route of Elimination: The principal route of excretion of cimetidine is the urine. Half Life: 2 hours

8.7 Biological Half-Life

Cimetidine's half-life is estimated to be around 2 hours.
ELEVEN PATIENTS WITH ASCITIC CIRRHOSIS & ELEVEN PATIENTS WITHOUT LIVER DISEASE RECEIVED 200 MG OF CIMETIDINE ORALLY AND IV. NO DIFFERENCES WERE OBSERVED IN CIMETIDINE T/2 BETWEEN THE 2 GROUPS. CIMETIDINE CLEARANCE WAS DIMINISHED IN CIRRHOTIC PATIENTS (0.426 + OR - 0.138 VERSUS 0.649 + OR - 0.163 L/HR/KG).
ALBIN H ET AL; GASTROENTEROL CLIN BIOL 7 (3): 251-5 (1983)
The elimination half-life in man is 1.9 to 2.2 hours.
Ellenhorn, M.J. and D.G. Barceloux. Medical Toxicology - Diagnosis and Treatment of Human Poisoning. New York, NY: Elsevier Science Publishing Co., Inc. 1988., p. 434
The plasma elimination half-life is about 2 hours.
American Medical Association, Council on Drugs. AMA Drug Evaluations Annual 1994. Chicago, IL: American Medical Association, 1994., p. 900
The half-time for elimination of cimetidine ... is 2 to 3 hours ... .
Gilman, A.G., T.W. Rall, A.S. Nies and P. Taylor (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 8th ed. New York, NY. Pergamon Press, 1990., p. 900

8.8 Mechanism of Action

Cimetidine binds to an H2-receptor located on the basolateral membrane of the gastric parietal cell, blocking histamine effects. This competitive inhibition results in reduced gastric acid secretion and a reduction in gastric volume and acidity.
H2 antagonists inhibit gastric acid secretion elicited by histamine & other H2 agonists in a dose-dependent, competitive manner; the degree of inhibition parallels the concentration of the drug in plasma over a wide range. The H2 antagonists also inhibit acid secretion elicited by gastrin &, to a lesser extent, by muscarinic agonists. Importantly, these drugs inhibit basal (fasting) & nocturnal acid secretion & that stimulated by food, sham feeding, fundic distention, & various pharmacological agents; this property reflects the vital role of histamine in mediating the effects of diverse stimuli. The H2 antagonists reduce both the volume of gastric juice secreted & its H+ concentration. The output of pepsin, which is secreted by the chief cells of gastric glands (mainly under cholinergic control), generally falls in parallel with the reduction in volume of gastric juice. /H2 antagonists/
Gilman, A.G., T.W. Rall, A.S. Nies and P. Taylor (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 8th ed. New York, NY. Pergamon Press, 1990., p. 899
Cimetidine blocks H2-receptors, which in part are responsible for the inflammatory response, in the cutaneous blood vessels of humans.
USP Convention. USPDI - Drug Information for the Health Care Professional. 16th ed. Volume I. Rockville, MD: U.S. Pharmaceutical Convention, Inc. 1996 (Plus updates)., p. 1612
The effects of cimetidine, omeprazole and atropine sulfate on the healing of acetic acid-induced gastric ulcers in rats with limited food intake time (9:00-10:00 am and 5:00-6:00 pm) were evaluated 15 days after the acid injection. Oral repeated admin of cimetidine (25-100 mg/kg twice daily) or omeprazole (10-50 mg/kg once daily) dose dependently accelerated ulcer healing. ... A single oral admin of omeprazole (50 mg/kg) or cimetidine (100 mg/kg) resulted in potent and long-lasting anti-acid secretory and gastrin-releasing actions. The degree and duration of anti-acid secretion by atropine sulfate were equal to those of cimetidine, but the elevation of gastrin release by atropine sulfate was weak and temporary. These results indicate that the gastric ulcers of rats with a limited food intake time are useful for evaluating the healing effects of cimetidine and omeprazole on gastric ulcers. In addition, the effects of both drugs may be related to the incr gastrin release rather than to the reduced acid secretion.
Ito M et al; Eur J Pharmacol 263 (3): 245-51 (1994)
Both KB-5492, a new anti-ulcer agent, and cimetidine, admin po at 25-200 mg/kg, dose-dependently prevented cysteamine (400 mg/kg, sc)-induced duodenal ulcers in rats with ED50 values of 63 and 40 mg/kg, respectively. Anti-ulcer doses of cimetidine, but not KB-5492, inhibited gastric acid hypersecretion induced by cysteamine (400 mg/kg, sc). In contrast, anti-ulcer doses of KB-5492, but not cimetidine, incr duodenal HC03- secretion in normal anesthetized rats. These findings suggest that KB-5492 prevents cysteamine-induced duodenal ulcers by stimulating duodenal HC03- secretion, whereas cimetidine does so by inhibiting cysteamine-induced gastric acid hypersecretion.
Morimoto Y et al; Jpn J Pharmacol 64 (3): 221-4 (1994)

8.9 Human Metabolite Information

8.9.1 Cellular Locations

  • Cytoplasm
  • Membrane

8.9.2 Metabolite Pathways

8.10 Biochemical Reactions

8.11 Transformations

9 Use and Manufacturing

9.1 Uses

EPA CPDat Chemical and Product Categories
The Chemical and Products Database, a resource for exposure-relevant data on chemicals in consumer products, Scientific Data, volume 5, Article number: 180125 (2018), DOI:10.1038/sdata.2018.125
MEDICATION

Use (kg; approx.) in Germany (2009): >1000

Use (kg) in USA (2002): 39500

Consumption (g per capita; approx.) in Germany (2009): 0.0122

Consumption (g per capita) in the USA (2002): 0.14

Excretion rate: 0.75

Calculated removal (%): 22

For the treatment and the management of acid-reflux disorders (GERD), peptic ulcer disease, heartburn, and acid indigestion.

9.1.1 Use Classification

Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients

9.2 Methods of Manufacturing

Reflux of N-cyano-s-dimethylguanidine and 5-methyl-4-[(2-aminoethyl)-thiomethyl] imidiazole in acetonitrile.
Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984., p. V11 697
Reaction of 5-methyl-4-[(2-aminoethyl)-thiomethyl] imidiazole with cyanodithioimidocarbonic acid dimethyl ester which gives the isothiourea and then reaction with methylamine.
Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984., p. V11 697
Refluxing N-methyl-N'-(2-((5-methyl-imidazole-4-yl)-methyl)thio)ethyl)-2-thiourea (metiamide) and lead cyanamide.
Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984., p. V11 697

9.3 Formulations / Preparations

BIOMAG, BRUMETIDINA, CIMET, NOTUL. /CIMETIDINE HYDROCHLORIDE/
Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989., p. 354

9.4 Consumption Patterns

Sales approximated $100 x 10+6/year as of mid-year 1977.
Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984., p. V12 488

10 Identification

10.1 Analytic Laboratory Methods

The liquid chromatograph is equipped with a 220 nm detector and 4.6 mm X 25 cm column that contains packing L1. The flow rate is about 2 ml/min. Sample volume is 50 ul. The relative standard deviation of the response for replicate injections is not more than 2.0%.
USP Convention. The United States Pharmacopeia XXII/National Formulary XVII. Rockville, MD: United States Pharmacopeial Convention, Inc., 1990., p. 310
Dissolve 2110 mg of Cimetidine, accurately weighed, in 75 ml of glacial acetic acid, and titrate with 0.1N perchloric acid VS, determining the end point potentiometrically.
USP Convention. The United States Pharmacopeia XXII/National Formulary XVII. Rockville, MD: United States Pharmacopeial Convention, Inc., 1990., p. 310

10.2 Clinical Laboratory Methods

A MICRO PROCEDURE FOR THE HIGH PRESSURE LIQUID CHROMATOGRAPHIC ANALYSIS OF CIMETIDINE IN SERUM OR PLASMA IS DESCRIBED. IT HAS BEEN USED IN STUDIES TO DETERMINE THE SERUM CONCN IN PATIENT RECEIVING THE DRUG BY BOTH THE ORAL & IV ROUTE.
SOLDIN SJ ET AL; THER DRUG MONIT 1 (3): 371-9 (1979)

11 Safety and Hazards

11.1 Hazards Identification

11.1.1 GHS Classification

Note
Pictograms displayed are for 99.3% (137 of 138) of reports that indicate hazard statements. This chemical does not meet GHS hazard criteria for 0.7% (1 of 138) of reports.
Pictogram(s)
Corrosive
Health Hazard
Signal
Danger
GHS Hazard Statements

H318 (39.1%): Causes serious eye damage [Danger Serious eye damage/eye irritation]

H360 (57.2%): May damage fertility or the unborn child [Danger Reproductive toxicity]

H373 (25.4%): May causes damage to organs through prolonged or repeated exposure [Warning Specific target organ toxicity, repeated exposure]

Precautionary Statement Codes

P203, P260, P264+P265, P280, P305+P354+P338, P317, P318, P319, P405, and P501

(The corresponding statement to each P-code can be found at the GHS Classification page.)

ECHA C&L Notifications Summary

Aggregated GHS information provided per 138 reports by companies from 11 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Reported as not meeting GHS hazard criteria per 1 of 138 reports by companies. For more detailed information, please visit ECHA C&L website.

There are 10 notifications provided by 137 of 138 reports by companies with hazard statement code(s).

Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown.

11.1.2 Hazard Classes and Categories

Eye Dam. 1 (39.1%)

Repr. 1B (57.2%)

STOT RE 2 (25.4%)

11.1.3 Health Hazards

SYMPTOMS: Symptoms of exposure to this compound can include, dermatitis, hair growth, rash, pruritus, erythema annulare centrifugum; anorexia, gastritis, gastrointestinal changes, diarrhea, constipation, nausea, ulcer perforation upon withdrawal; hepatitis, jaundice, increases in serum creatinine and liver enzymes, changes in kidney tubules, interstitial nephritis and possible renal failure; hypotension, increased body temperature, sweating; muscle weakness and/or pain; endocrine changes, gynecomastia; leukopenia, agranulocytosis, thrombocytopenia; transient psychosis, confusion, disorientation, agitation, hallucinations, dizziness, somnolence, headache, fatigue, malaise; loss of libido and impotence.

ACUTE/CHRONIC HAZARDS: When heated to decomposition this compound emits very toxic fumes of NOx and SOx. (NTP, 1992)

National Toxicology Program, Institute of Environmental Health Sciences, National Institutes of Health (NTP). 1992. National Toxicology Program Chemical Repository Database. Research Triangle Park, North Carolina.

11.1.4 Fire Hazards

Flash point data for this compound are not available. It is probably combustible. (NTP, 1992)
National Toxicology Program, Institute of Environmental Health Sciences, National Institutes of Health (NTP). 1992. National Toxicology Program Chemical Repository Database. Research Triangle Park, North Carolina.

11.1.5 Hazards Summary

Asthma reported in a pharmaceutical worker; [Malo]

11.2 First Aid Measures

11.2.1 First Aid

EYES: First check the victim for contact lenses and remove if present. Flush victim's eyes with water or normal saline solution for 20 to 30 minutes while simultaneously calling a hospital or poison control center. Do not put any ointments, oils, or medication in the victim's eyes without specific instructions from a physician. IMMEDIATELY transport the victim after flushing eyes to a hospital even if no symptoms (such as redness or irritation) develop.

SKIN: IMMEDIATELY flood affected skin with water while removing and isolating all contaminated clothing. Gently wash all affected skin areas thoroughly with soap and water. If symptoms such as redness or irritation develop, IMMEDIATELY call a physician and be prepared to transport the victim to a hospital for treatment.

INHALATION: IMMEDIATELY leave the contaminated area; take deep breaths of fresh air. If symptoms (such as wheezing, coughing, shortness of breath, or burning in the mouth, throat, or chest) develop, call a physician and be prepared to transport the victim to a hospital. Provide proper respiratory protection to rescuers entering an unknown atmosphere. Whenever possible, Self-Contained Breathing Apparatus (SCBA) should be used; if not available, use a level of protection greater than or equal to that advised under Protective Clothing.

INGESTION: DO NOT INDUCE VOMITING. If the victim is conscious and not convulsing, give 1 or 2 glasses of water to dilute the chemical and IMMEDIATELY call a hospital or poison control center. Be prepared to transport the victim to a hospital if advised by a physician. If the victim is convulsing or unconscious, do not give anything by mouth, ensure that the victim's airway is open and lay the victim on his/her side with the head lower than the body. DO NOT INDUCE VOMITING. IMMEDIATELY transport the victim to a hospital. (NTP, 1992)

National Toxicology Program, Institute of Environmental Health Sciences, National Institutes of Health (NTP). 1992. National Toxicology Program Chemical Repository Database. Research Triangle Park, North Carolina.

11.3 Fire Fighting

Fires involving this material can be controlled with a dry chemical, carbon dioxide or Halon extinguisher. (NTP, 1992)
National Toxicology Program, Institute of Environmental Health Sciences, National Institutes of Health (NTP). 1992. National Toxicology Program Chemical Repository Database. Research Triangle Park, North Carolina.

11.4 Accidental Release Measures

11.4.1 Disposal Methods

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

11.5 Handling and Storage

11.5.1 Nonfire Spill Response

SMALL SPILLS AND LEAKAGE: If you spill this chemical, FIRST REMOVE ALL SOURCES OF IGNITION. You should then dampen the solid spill material with 60-70% methanol, then transfer the dampened material to a suitable container. Use absorbent paper dampened with methanol to pick up any remaining material. Your contaminated clothing and absorbent paper should be sealed in a vapor-tight plastic bag for eventual disposal. Solvent-wash contaminated surfaces with 60-70% methanol followed by washing with a soap and water solution. Do not reenter the contaminated area until the Safety Officer (or other responsible person) has verified that the area has been properly cleaned.

STORAGE PRECAUTIONS: You should store this material under ambient conditions. (NTP, 1992)

National Toxicology Program, Institute of Environmental Health Sciences, National Institutes of Health (NTP). 1992. National Toxicology Program Chemical Repository Database. Research Triangle Park, North Carolina.

11.5.2 Storage Conditions

Preserve in tight, light resistant containers at controlled room temperatures.
USP Convention. The United States Pharmacopeia XXII/National Formulary XVII. Rockville, MD: United States Pharmacopeial Convention, Inc., 1990., p. 310

11.6 Exposure Control and Personal Protection

11.6.1 Personal Protective Equipment (PPE)

RECOMMENDED RESPIRATOR: Where the neat test chemical is weighed and diluted, wear a NIOSH-approved half face respirator equipped with an organic vapor/acid gas cartridge (specific for organic vapors, HCl, acid gas and SO2) with a dust/mist filter. (NTP, 1992)
National Toxicology Program, Institute of Environmental Health Sciences, National Institutes of Health (NTP). 1992. National Toxicology Program Chemical Repository Database. Research Triangle Park, North Carolina.

11.7 Stability and Reactivity

11.7.1 Air and Water Reactions

Slightly water soluble.

11.7.2 Reactive Group

Amines, Phosphines, and Pyridines

Sulfides, Organic

Nitriles

11.8 Regulatory Information

11.8.1 FDA Requirements

Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392).
21 CFR 200-299, 300-499, 820, and 860 (4/1/93)

11.9 Other Safety Information

Chemical Assessment

IMAP assessments - Guanidine, N-cyano-N'-methyl-N''-[2-[[(5-methyl-1H-imidazol-4-yl)methyl]thio]ethyl]-: Environment tier I assessment

IMAP assessments - Guanidine, N-cyano-N'-methyl-N''-[2-[[(5-methyl-1H-imidazol-4-yl)methyl]thio]ethyl]-: Human health tier I assessment

11.9.1 Special Reports

Dixon JS, Page MC; Interactions Between Non-steroidal Anti-inflammatory Drugs and H2-Receptor Antagonists or Prostaglandin Analogues; Rheumatol Int 11 (1): 13-8 (1991). Published pharmacokinetic studies investigating possible interaction between H2-receptor antagonists (n = 22) or prostaglandin analogues (n = 6) and nonsteroidal anti-inflammatory drugs have been reviewed.
Cimetidine, an H2-receptor antagonist, has been shown to enhance a variety of immunologic functions both in vivo and in vitro because of its inhibitory effects on suppressor-cell function.[Kumar A; Cimetidine: An Immunomodulator; DICP 24 (3): 289-95 (1990)]
Feldman M, Burton ME; Histamine2-Receptor Antagonists: Standard Therapy for Acid-Peptic Diseases. Part 2; N Engl J Med 323 (Dec 20): 1749-44 (1990). A review of 4 histamine H2 receptor blockers, cimetidine, famotidine, ranitidine and nizatidine, is presented, including a discussion of the results of multiple studies of therapeutic efficacy of H2 blockers for duodenal ulcer, gastric ulcer, Zollinger-Ellison syndrome, gastroesophageal reflux disease, and acute stress ulcers and erosions.
Lee RM, McDowall RD; Recent Advances in Pharmaceutical Chemistry. Review 2. Histamine H2-Receptor Antagonists; J Clin Hosp Pharm 11 (Dec): 389-408 (1986). The concept of histamine receptors and the pharmacological actions, structure-activity relationships and pharmacokinetics of H2-antagonists including cimetidine, ranitidine, oxmetidine, lupitidine and loxtidine are reviewed
For more Special Reports (Complete) data for CIMETIDINE (7 total), please visit the HSDB record page.

12 Toxicity

12.1 Toxicological Information

12.1.1 Toxicity Summary

Cimetidine binds to an H2-receptor located on the basolateral membrane of the gastric parietal cell, blocking histamine effects. This competitive inhibition results in reduced gastric acid secretion and a reduction in gastric volume and acidity.

12.1.2 USGS Health-Based Screening Levels for Evaluating Water-Quality

Chemical
Cimetidine
Chemical Classes
Pharmaceutical
Reference
Smith, C.D. and Nowell, L.H., 2024. Health-Based Screening Levels for evaluating water-quality data (3rd ed.). DOI:10.5066/F71C1TWP

12.1.3 Hepatotoxicity

Chronic therapy with cimetidine has been associated with minor elevations in serum aminotransferase levels in 1% to 4% of patients, but similar rates were reported in placebo recipients. The ALT elevations were usually asymptomatic and transient and usually resolved even without dose modification. Several instances of clinically apparent liver injury have been reported in patients receiving cimetidine, but the time to onset and pattern of injury has varied greatly. Onset can be as short as a few days to as long as 7 months, and the serum enzyme pattern varies from hepatocellular to cholestatic, most cases having a “mixed” hepatocellular-cholestatic pattern of injury (Cases 1 and 2). The injury is rarely severe and resolves within 4 to 12 weeks of stopping cimetidine. Liver biopsy histology often shows prominent centrolobular necrosis. Immunoallergic features (rash, fever, eosinophilia) are uncommon, as is autoantibody formation.

Likelihood score: B (highly likely cause of clinically apparent liver injury).

12.1.4 Drug Induced Liver Injury

Compound
cimetidine
DILI Annotation
Less-DILI-Concern
Severity Grade
2
Label Section
Adverse reactions
References

M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. FDA-Approved Drug Labeling for the Study of Drug-Induced Liver Injury, Drug Discovery Today, 16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007

M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank: the largest reference drug list ranked by the risk for developing drug-induced liver injury in humans. Drug Discov Today 2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015

12.1.5 Evidence for Carcinogenicity

Evaluation: There is inadequate evidence for the carcinogenicity of cimetidine in humans. There is inadequate evidence for the carcinogenicity of cimetidine in experimental animals. Overall evaluation: Cimetidine is not classifiable as to its carcinogenicity to humans (Group 3).
IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: https://monographs.iarc.fr/ENG/Classification/index.php, p. 50 254 (1990)

12.1.6 Carcinogen Classification

1 of 2
IARC Carcinogenic Agent
Cimetidine
IARC Carcinogenic Classes
Group 3: Not classifiable as to its carcinogenicity to humans
IARC Monographs
Volume 50: (1990) Pharmaceutical Drugs
2 of 2
Carcinogen Classification
3, not classifiable as to its carcinogenicity to humans. (L135)

12.1.7 Effects During Pregnancy and Lactation

◉ Summary of Use during Lactation

Maternal cimetidine doses of 1000 to 1200 mg daily result in infant dosages that are much less than reported neonatal dosages of 5 to 10 mg/kg daily. Cimetidine would not be expected to cause any adverse effects in breastfed infants, especially if the infant is older than 2 months. However, because of its potential for causing hepatic enzyme inhibition, other drugs might be preferred. Cimetidine can increase serum prolactin and it has been used, but not validated, as a galactogogue.

◉ Effects in Breastfed Infants

Relevant published information was not found as of the revision date.

◉ Effects on Lactation and Breastmilk

Histamine H2-receptor blockade is known to stimulate prolactin secretion. In addition, cimetidine may have additional, nonspecific actions that stimulate prolactin secretion. Oral cimetidine doses of 400 mg 4 times daily increased serum prolactin by 50 to 112% in 6 patients. Cimetidine has caused dose-related gynecomastia and galactorrhea in men and nonnursing women. The prolactin level in a mother with established lactation may not affect her ability to breastfeed.

One clinician reported that she used cimetidine 200 or 300 mg 4 times daily to nursing mothers with a marginal or low milk supply. Subjective reports indicated an increase in milk supply.

12.1.8 Exposure Routes

Oral, rapid 60-70%

12.1.9 Symptoms

Symptoms of overdose include nausea, vomiting, diarrhea, increased saliva production, difficulty breathing, and a fast heartbeat.

12.1.10 Adverse Effects

Asthma - Reversible bronchoconstriction (narrowing of bronchioles) initiated by the inhalation of irritating or allergenic agents.

12.1.11 Acute Effects

12.1.12 Treatment

The usual measures to remove unabsorbed material from the gastrointestinal tract, clinical monitoring and supportive therapy should be employed. (L1712)
L1712: RxList: The Internet Drug Index (2009). http://www.rxlist.com/

12.1.13 Interactions

OUTPUT OF INTRINSIC FACTOR OF CASTLE IN RESPONSE TO BETAZOLE IS INHIBITED BY CIMETIDINE, BUT BASAL SECRETION OF THE PROTEIN IS ONLY SLIGHTLY AFFECTED AND NO EVIDENCE OF DEFICIENT ABSORPTION OF VITAMIN B12 HAS BEEN NOTED, EVEN DURING LONG-TERM TREATMENT.
Gilman, A. G., L. S. Goodman, and A. Gilman. (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 6th ed. New York: Macmillan Publishing Co., Inc. 1980., p. 631
Antacids reduce the oral bioavailability of concomitantly administered cimetidine or ranitidine. ... These drugs probably should be given one hour apart.
American Medical Association, Council on Drugs. AMA Drug Evaluations Annual 1994. Chicago, IL: American Medical Association, 1994., p. 900
REDUCED HEPATIC BLOOD FLOW /AFTER ADMIN OF CIMETIDINE/ HAS BEEN REPORTED TO PROLONG THE CLEARANCE AND, THEREFORE, EXAGGERATE THE EFFECTS OF MORPHINE ... AND LIDOCAINE.
American Medical Association, AMA Department of Drugs. AMA Drug Evaluations. 5th ed. Chicago: American Medical Association, 1983., p. 1267
SIX OUT OF 8 PATIENTS TREATED WITH CARMUSTINE, 80 MG/SQ M/DAY FOR 3 DAYS, CIMETIDINE, 300 MG 6 HOURLY, AND STEROIDS DEMONSTRATED MARKED LEUCOPENIA AND THROMBOCYTOPENIA ... AFTER FIRST ADMIN. IN COMPARISON ONLY 6 OUT OF 40 PATIENTS WHO WERE SIMILARLY TREATED, BUT WITHOUT CIMETIDINE, SHOWED COMPARABLE WHITE CELL AND PLATELET DEPRESSION.
Stockley, I.H. Drug Interactions. Boston: Blackwell Scientific Publications, 1981., p. 280
For more Interactions (Complete) data for CIMETIDINE (37 total), please visit the HSDB record page.

12.1.14 Human Toxicity Excerpts

ACUTE RENAL FAILURE DEVELOPED IN A PATIENT AFTER SHE RECEIVED CIMETIDINE THERAPY. A RENAL BIOPSY SPECIMEN SHOWED ACUTE INTERSTITIAL NEPHRITIS. WITHDRAWAL OF CIMETIDINE THERAPY LED TO IMPROVEMENT OF RENAL FUNCTION.
KAYE WA ET AL; ARCH INTERN MED 143 (4): 811-2 (1983)
THREE EPISODES, IN WHICH PATIENTS SUFFERED A CARDIAC ARREST IN CLOSE ASSOC WITH RECEIVING A BOLUS IV INJECTION OF CIMETIDINE, ARE REPORTED.
SHAW RG ET AL; MED J AUST 2 (11): 629-30 (1980)
THREE PATIENTS ARE PRESENTED WHO EXPERIENCED AGITATION, DISORIENTATION, AND HALLUCINATIONS WHILE BEING TREATED WITH CIMETIDINE.
YUDOFSKY SC ET AL; GEN HOSP PSYCHIATRY 2 (3): 233-6 (1980)
A HEALTHY YOUNG WOMAN DEVELOPED MARKED DEPRESSION AND LOSS OF LIBIDO WHILE TAKING CIMETIDINE. HER SYMPTOMS PROMPTLY RESOLVED AFTER DISCONTINUATION OF CIMETIDINE SUGGESTING THAT HER SYMPTOMS REPRESENT AN ADVERSE DRUG REACTION.
PIERCE JR JR; AM J MED SCI 286 (3): 31-4 (1983)
For more Human Toxicity Excerpts (Complete) data for CIMETIDINE (14 total), please visit the HSDB record page.

12.1.15 Non-Human Toxicity Excerpts

THE GENOTOXICITY OF CIMETIDINE WAS EXAM IN THE HEPATOCYTE PRIMARY CULTURE/DNA-REPAIR TEST AND BY THE DNA-DAMAGE/ALKALINE-ELUTION ASSAY. A DOSE-DEPENDENT AMT OF UNSCHEDULED DNA SYNTHESIS WAS ELICITED BY CIMETIDINE, WHEREAS DNA FRAGMENTATION OCCURRED ONLY IN HEPATOCYTES EXPOSED TO THE HIGHEST (3 MILLIMOLAR) CONCN OF THE DRUG.
MARTELLI A ET AL; MUTAT RES 120 (2-3): 133-7 (1983)
EXPOSURE OF RATS TO CIMETIDINE DURING INTRAUTERINE LIFE AND THE IMMEDIATE NEONATAL PERIOD RESULTS IN HYPOANDROGENIZATION IN ADULT LIFE WITH DECR WT OF ANDROGEN-DEPENDENT TISSUES AND DECR CONCN OF TESTOSTERONE. MOREOVER, SEXUAL BEHAVIOR PATTERNS IN ADULT LIFE ARE DISTURBED AS SHOWN BY A LACK OF SEXUAL MOTIVATION AND DECR PERFORMANCE.
ANAND S, VAN THIEL DH; SCIENCE 218 (4571): 493-4 (1982)
In a 2 year study in rats receiving cimetidine dosages of 150, 378, and 950 mg/kg daily (approximately 8-48 times the recommended human dosages), a small increase in the incidence of benign Leydig cell tumors in each dosage group compared with the control group was observed. In a subsequent 2 year study, the incidence of these benign Leydig cell tumors was increased compared with controls in rats receiving 378 or 950 mg/kg of cimetidine but not in those receiving 150 mg/kg. These tumors were common in control as well as treated groups, and the differences became apparent only in aged rats.
McEvoy G.K. (ed.). American Hospital Formulary Service-Drug Information 96. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 1996 (Plus Supplements)., p. 2143
Cimetidine, a widely prescribed, potent histamine H2-receptor antagonist, is unrelatedly a mild antiandrogen. Cimetidine was administered in pregnant female rat drinking water at several levels reflecting both human and rat therapeutic like doses from day 17 of gestation through day 7 of lactation. Except for the highest dose of cimetidine (4.0 mg/ml drinking water) the drug had no effect on the dams' food and water consumption or body weight gain. In general, feminine sexual development as measured by pubertal on set, reproductive organ weights and adult estrous cyclicity, was unaffected by perinatal exposure to cimetidine. Similarly, early exposure to the drug had little effect on masculine sexual development. The developmental profile of serum dehydroepiandrosterone, androstenedione, testosterone and 5 alpha-dihydrotestosterone when measured at 1, 4 and 18 weeks of age, was unaffected by perinatal exposure to cimetidine. Furthermore, serum androgen concentrations and seminal vesicle weights following orchiectomy and androgen replacement were the same in control and cimetidine exposed rats. In contrast, pituitary weights of adult males exposed to maternally administered cimetidine appeared to be insensitive to androgen regulation. However, taken in totality, the results do not support the concept that cimetidine is a reproductive teratogen.
Shapiro BH et al; Toxicol Lett 44 (3): 315-29 (1988)
For more Non-Human Toxicity Excerpts (Complete) data for CIMETIDINE (21 total), please visit the HSDB record page.

12.1.16 Protein Binding

In humans, approximately 22.5% of cimetidine is plasma protein bound.

12.2 Ecological Information

12.2.1 Environmental Fate / Exposure Summary

Cimetidine's production and use as an anti-ulcerative may result in its release to the environment through various waste streams. If released to soil, cimetidine should have very high mobility. However, cimetidine will exist in both the undissociated and cation form under environmental conditions (pH 5-9), because of its pKa of 6.8; no experimental data are available to indicate whether the cation will adsorb to soil more strongly than its estimated Koc value for the undissociated form indicates. Volatilization of cimetidine should not be important from moist or dry soil surfaces. Insufficient data are available to determine the rate or importance of biodegradation of cimetidine in soil or water. If released to water, cimetidine would not adsorb to suspended solids and sediment, although the cation may adsorb to clay particles. Cimetidine will be essentially non-volatile from water surfaces. An estimated BCF value of 1.2 suggests that cimetidine will not bioconcentrate in aquatic organisms. If released to the atmosphere, cimetidine will exist primarily in the particulate phase. Vapor-phase cimetidine is degraded in the atmosphere by reaction with photochemically produced hydroxyl radicals with an estimated half-life of about 1.8 hours. Particulate-phase cimetidine may be physically removed from the air by wet deposition. Cimetidine is an antagonist to Histamine H2 receptors especially in the treatment of duodenal and gastric ulcers(1); therefore, many in the general population will be consuming to cimetidine by ingestion. In occupational settings, workers may be exposed to cimetidine through inhalation of dust and through eye and skin contact. (SRC)

12.2.2 Artificial Pollution Sources

Cimetidine's production and use as an anti-ulcerative(1) (an antagonist to Histamine H2 receptors especially in the treatment of duodenal and gastric ulcers(2)), may result in its release to the environment through various waste streams(SRC).
(1) Budavari S; The Merck Index - Encyclopedia of Chemicals, Drugs, and Biologicals. Rahway, NJ: Merck and Co Inc pg 354 (1989)
(2) Windholz M et al; The Merck Index 10th ed. Rahway, NJ: Merck & Co Inc (1983)

12.2.3 Environmental Fate

TERRESTRIAL FATE: Based on a recommended classification scheme(1), an estimated Koc value of 39(SRC), determined from an experimental log Kow(2) and a recommended regression-derived equation(3), indicates that cimetidine should have very high mobility in soil(SRC). However, cimetidine will exist in both the undissociated and cation form under environmental conditions (pH 5-9), (pKa of 6.8)(6); no experimental data are available to indicate whether the cation will adsorb to soil more strongly than its estimated Koc value for the undissociated form indicates(SRC). Volatilization of cimetidine should not be important from moist soil surfaces(SRC) given an estimated Henry's Law constant of 9.5X10-16 atm-cu m/mole(SRC), using a recommended regression equation(4) or from dry soil surfaces(SRC) based on an estimated vapor pressure of 5.5X10-9 mm Hg(SRC), using a fragment constant method(5). Insufficient data are available to determine the rate or importance of biodegradation of cimetidine in soil(SRC).
(1) Swann RL et al; Res Rev 85: 23 (1983)
(2) Hansch C, Leo AJ; Medchem Project Issue No 24 Claremont, CA: Pomona College (1985)
(3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 4-9 (1990)
(4) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991)
(5) Lyman WJ; p 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE(eds), Boca Raton, FL: CRC Press (1985)
(6) Tomlinson E, Hafkenscheid TL; pp 101-41 in Partition Coefficient; Determination and Estimation. Dunn JIII et al. ed. Elmsford, NY: Pergamon Press (1986)
AQUATIC FATE: Based on a recommended classification scheme(1), an estimated Koc value of 39(SRC), determined from an experimental log Kow(2) and a recommended regression-derived equation(1), indicates that cimetidine would not adsorb to suspended solids and sediment(SRC) in the water. However, cimetidine will exist in both the undissociated and cation form under environmental conditions (pH 5-9), (pKa of 6.8)(5);no experimental data are available to indicate whether the cation will adsorb to soil more strongly than its estimated Koc value for the undissociated form indicates(SRC). Cimetidine will be essentially non-volatile from water surfaces based on an estimated Henry's Law constant of 9.5X10-16 atm-cu m/mole(SRC), developed using a fragment constant estimation method(3). An estimated BCF value of 1.2(1,SRC), from an experimental log Kow(2), suggests that cimetidine will not bioconcentrate in aquatic organisms(SRC), according to a recommended classification scheme(4). Insufficient data are available to determine the rate or importance of biodegradation of cimetidine in water(SRC).
(1) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 4-9, 5-4, 5-10, 15-1 to 15-29 (1990)
(2) Hansch C, Leo AJ; Medchem Project Issue No 24 Claremont, CA: Pomona College (1985)
(3) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991)
(4) Franke C et al; Chemosphere 29: 1501-14 (1994)
(5) Tomlinson E, Hafkenscheid TL; pp 101-41 in Partition Coefficient; Determination and Estimation. Dunn JIII et al. ed. Elmsford, NY: Pergamon Press (1986)
ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), cimetidine, which has an estimated vapor pressure of 5.5X10-9 mm Hg at 25 °C(2,SRC), will exist primarily in the particulate phase in the ambient atmosphere. Vapor-phase cimetidine is degraded in the atmosphere by reaction with photochemically produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be about 1.8 hours(3,SRC). Particulate-phase cimetidine may be physically removed from the air by wet deposition(SRC).
(1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988)
(2) Lyman WJ; p 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE (eds), Boca Raton, FL: CRC Press (1985)
(3) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993)

12.2.4 Environmental Abiotic Degradation

The rate constant for the vapor-phase reaction of cimetidine with photochemically produced hydroxyl radicals has been estimated as 2.1X10-10 cu cm/molecule-sec at 25 °C(SRC) using a structure estimation method(1,SRC). This corresponds to an atmospheric half-life of about 1.8 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1,SRC).
(1) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993)

12.2.5 Environmental Bioconcentration

An estimated BCF value of 1.2 was calculated for cimetidine(SRC), using an experimental log Kow of 0.40(1) and a recommended regression-derived equation(2). According to a recommended classification scheme(3), this BCF value suggests that bioconcentration in aquatic organisms will not be an important fate process(SRC).
(1) Hansch C, Leo AJ; Medchem Project Issue No 24 Claremont, CA: Pomona College (1985)
(2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 5-4, 5-10 (1990)
(3) Franke C et al; Chemosphere 29: 1501-14 (1994)

12.2.6 Soil Adsorption / Mobility

The Koc of cimetidine is estimated as approximately 39(SRC), using an experimental log Kow of 0.40(1) and a regression-derived equation(2,SRC). According to a recommended classification scheme(3), this estimated Koc value suggests that cimetidine should have very high mobility in soil(SRC). However, cimetidine will exist in both the undissociated and cation form under environmental conditions (pH 5-9), (pKa of 6.8)(4), and no experimental data are available to indicate whether the cation will adsorb to soil more strongly than its estimated Koc value for the undissociated form indicates(SRC).
(1) Hansch C, Leo AJ; Medchem Project Issue No 24 Claremont, CA: Pomona College (1985)
(2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 4-9 (1990)
(3) Swann RL et al; Res Rev 85: 23 (1983)
(4) Tomlinson E, Hafkenscheid TL; pp 101-41 in Partition Coefficient; Determination and Estimation. Dunn JIII et al. ed. Elmsford, NY: Pergamon Press (1986)

12.2.7 Volatilization from Water / Soil

The Henry's Law constant for cimetidine is estimated as 9.5X10-16 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This value indicates that cimetidine will be essentially nonvolatile from water surfaces(2,SRC). Cimetidine's vapor pressure, 5.5X10-9 mm Hg(3,SRC) and Henry's Law constant(1,SRC) indicate that volatilization from dry and moist soil surfaces should not occur(SRC).
(1) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991)
(2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 15-1 to 15-29 (1990)
(3) Lyman WJ; p 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE(eds), Boca Raton, FL: CRC Press (1985)

12.2.8 Milk Concentrations

Drug concentrated in human milk. /from Table 6/
Report of the American Academy of Pediatrics Committee on Drugs in Pediatrics 93 (1): 140 (1994)

12.2.9 Probable Routes of Human Exposure

Cimetidine is an antagonist to Histamine H2 receptors especially in the treatment of duodenal and gastric ulcers(1); therefore, many in the general population will be consuming cimetidine by ingestion. In occupational settings, workers may be exposed to cimetidine through inhalation of dust and through eye and skin contact(SRC).
(1) Windholz M et al; The Merck Index 10th ed. Rahway, NJ: Merck & Co Inc (1983)
NIOSH (NOES Survey 1981-1983) has statistically estimated that 11,101 workers (9,114 of these are female) are potentially exposed to cimetidine in the USA(1).
(1) NIOSH; National Occupational Exposure Survey (NOES) (1983)

12.2.10 Body Burden

Dialysis fluid from human subjects injected with 300 mg cimetidine, contained 1.1-4.3% of the original dose after 24 hours(1). Urine samples from human subjects fed 400 mg cimetidine contained an average of 157.6 mg after 48 hours(1).
(1) Cone MV et al; National Body-Burden Database Chemicals Identified in Human Biological Media, 1984 Volume VII, Part 1, 2, 3; EPA-560-5-84-003 Vol 7 Pt 1, 2, 3 (1986)

13 Associated Disorders and Diseases

Associated Occupational Diseases with Exposure to the Compound
Asthma, occupational [Category: Airway Disease]

14 Literature

14.1 Consolidated References

14.2 NLM Curated PubMed Citations

14.3 Springer Nature References

14.4 Thieme References

14.5 Wiley References

14.6 Nature Journal References

14.7 Chemical Co-Occurrences in Literature

14.8 Chemical-Gene Co-Occurrences in Literature

14.9 Chemical-Disease Co-Occurrences in Literature

15 Patents

15.1 Depositor-Supplied Patent Identifiers

15.2 WIPO PATENTSCOPE

15.3 Chemical Co-Occurrences in Patents

15.4 Chemical-Disease Co-Occurrences in Patents

15.5 Chemical-Gene Co-Occurrences in Patents

16 Interactions and Pathways

16.1 Protein Bound 3D Structures

16.2 Chemical-Target Interactions

16.3 Drug-Drug Interactions

16.4 Drug-Food Interactions

Take with food. Food increases bioavailability. For prophylaxis of gastric symptoms, take cimetidine 30-60 minutes prior to food administration.

16.5 Pathways

17 Biological Test Results

17.1 BioAssay Results

18 Classification

18.1 MeSH Tree

18.2 NCI Thesaurus Tree

18.3 ChEBI Ontology

18.4 KEGG: Drug

18.5 KEGG: USP

18.6 KEGG: ATC

18.7 KEGG: Target-based Classification of Drugs

18.8 KEGG: JP15

18.9 KEGG: Risk Category of Japanese OTC Drugs

18.10 KEGG: OTC drugs

18.11 KEGG: Drug Groups

18.12 KEGG: Drug Classes

18.13 WHO ATC Classification System

18.14 FDA Pharm Classes

18.15 ChemIDplus

18.16 CAMEO Chemicals

18.17 IUPHAR / BPS Guide to PHARMACOLOGY Target Classification

18.18 ChEMBL Target Tree

18.19 UN GHS Classification

18.20 EPA CPDat Classification

18.21 NORMAN Suspect List Exchange Classification

18.22 CCSBase Classification

18.23 EPA DSSTox Classification

18.24 International Agency for Research on Cancer (IARC) Classification

18.25 FDA Drug Type and Pharmacologic Classification

18.26 EPA Substance Registry Services Tree

18.27 MolGenie Organic Chemistry Ontology

19 Information Sources

  1. Australian Industrial Chemicals Introduction Scheme (AICIS)
    Guanidine, N-cyano-N'-methyl-N''-[2-[[(5-methyl-1H-imidazol-4-yl)methyl]thio]ethyl]-
    https://services.industrialchemicals.gov.au/search-assessments/
  2. CAMEO Chemicals
    LICENSE
    CAMEO Chemicals and all other CAMEO products are available at no charge to those organizations and individuals (recipients) responsible for the safe handling of chemicals. However, some of the chemical data itself is subject to the copyright restrictions of the companies or organizations that provided the data.
    https://cameochemicals.noaa.gov/help/reference/terms_and_conditions.htm?d_f=false
    CAMEO Chemical Reactivity Classification
    https://cameochemicals.noaa.gov/browse/react
  3. CAS Common Chemistry
    LICENSE
    The data from CAS Common Chemistry is provided under a CC-BY-NC 4.0 license, unless otherwise stated.
    https://creativecommons.org/licenses/by-nc/4.0/
  4. ChemIDplus
    ChemIDplus Chemical Information Classification
    https://pubchem.ncbi.nlm.nih.gov/source/ChemIDplus
  5. DrugBank
    LICENSE
    Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode)
    https://www.drugbank.ca/legal/terms_of_use
  6. DTP/NCI
    LICENSE
    Unless otherwise indicated, all text within NCI products is free of copyright and may be reused without our permission. Credit the National Cancer Institute as the source.
    https://www.cancer.gov/policies/copyright-reuse
  7. EPA DSSTox
    CompTox Chemicals Dashboard Chemical Lists
    https://comptox.epa.gov/dashboard/chemical-lists/
  8. European Chemicals Agency (ECHA)
    LICENSE
    Use of the information, documents and data from the ECHA website is subject to the terms and conditions of this Legal Notice, and subject to other binding limitations provided for under applicable law, the information, documents and data made available on the ECHA website may be reproduced, distributed and/or used, totally or in part, for non-commercial purposes provided that ECHA is acknowledged as the source: "Source: European Chemicals Agency, http://echa.europa.eu/". Such acknowledgement must be included in each copy of the material. ECHA permits and encourages organisations and individuals to create links to the ECHA website under the following cumulative conditions: Links can only be made to webpages that provide a link to the Legal Notice page.
    https://echa.europa.eu/web/guest/legal-notice
  9. FDA Global Substance Registration System (GSRS)
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  10. Hazardous Substances Data Bank (HSDB)
  11. Human Metabolome Database (HMDB)
    LICENSE
    HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications.
    http://www.hmdb.ca/citing
  12. BindingDB
    LICENSE
    All data curated by BindingDB staff are provided under the Creative Commons Attribution 3.0 License (https://creativecommons.org/licenses/by/3.0/us/).
    https://www.bindingdb.org/rwd/bind/info.jsp
    (Cimetidine) N-Methyl-N''''-[2-(5-methyl-1H-imidazol-4-ylmethylsulfanyl)-ethyl]-guanidine,cyanide
    https://www.bindingdb.org/rwd/bind/chemsearch/marvin/MolStructure.jsp?monomerid=22889
  13. ChEMBL
    LICENSE
    Access to the web interface of ChEMBL is made under the EBI's Terms of Use (http://www.ebi.ac.uk/Information/termsofuse.html). The ChEMBL data is made available on a Creative Commons Attribution-Share Alike 3.0 Unported License (http://creativecommons.org/licenses/by-sa/3.0/).
    http://www.ebi.ac.uk/Information/termsofuse.html
  14. Comparative Toxicogenomics Database (CTD)
    LICENSE
    It is to be used only for research and educational purposes. Any reproduction or use for commercial purpose is prohibited without the prior express written permission of NC State University.
    http://ctdbase.org/about/legal.jsp
  15. Drug Gene Interaction database (DGIdb)
    LICENSE
    The data used in DGIdb is all open access and where possible made available as raw data dumps in the downloads section.
    http://www.dgidb.org/downloads
  16. IUPHAR/BPS Guide to PHARMACOLOGY
    LICENSE
    The Guide to PHARMACOLOGY database is licensed under the Open Data Commons Open Database License (ODbL) https://opendatacommons.org/licenses/odbl/. Its contents are licensed under a Creative Commons Attribution-ShareAlike 4.0 International License (http://creativecommons.org/licenses/by-sa/4.0/)
    https://www.guidetopharmacology.org/about.jsp#license
    Guide to Pharmacology Target Classification
    https://www.guidetopharmacology.org/targets.jsp
  17. Therapeutic Target Database (TTD)
  18. Toxin and Toxin Target Database (T3DB)
    LICENSE
    T3DB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (T3DB) and the original publication.
    http://www.t3db.ca/downloads
  19. ChEBI
  20. FDA Pharm Classes
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  21. LiverTox
  22. NCI Thesaurus (NCIt)
    LICENSE
    Unless otherwise indicated, all text within NCI products is free of copyright and may be reused without our permission. Credit the National Cancer Institute as the source.
    https://www.cancer.gov/policies/copyright-reuse
  23. Open Targets
    LICENSE
    Datasets generated by the Open Targets Platform are freely available for download.
    https://platform-docs.opentargets.org/licence
  24. CCSbase
    CCSbase Classification
    https://ccsbase.net/
  25. ClinicalTrials.gov
    LICENSE
    The ClinicalTrials.gov data carry an international copyright outside the United States and its Territories or Possessions. Some ClinicalTrials.gov data may be subject to the copyright of third parties; you should consult these entities for any additional terms of use.
    https://clinicaltrials.gov/ct2/about-site/terms-conditions#Use
  26. Haz-Map, Information on Hazardous Chemicals and Occupational Diseases
    LICENSE
    Copyright (c) 2022 Haz-Map(R). All rights reserved. Unless otherwise indicated, all materials from Haz-Map are copyrighted by Haz-Map(R). No part of these materials, either text or image may be used for any purpose other than for personal use. Therefore, reproduction, modification, storage in a retrieval system or retransmission, in any form or by any means, electronic, mechanical or otherwise, for reasons other than personal use, is strictly prohibited without prior written permission.
    https://haz-map.com/About
  27. Crystallography Open Database (COD)
    LICENSE
    All data in the COD and the database itself are dedicated to the public domain and licensed under the CC0 License. Users of the data should acknowledge the original authors of the structural data.
    https://creativecommons.org/publicdomain/zero/1.0/
  28. DailyMed
  29. Drug Induced Liver Injury Rank (DILIrank) Dataset
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  30. Drugs and Lactation Database (LactMed)
  31. Drugs@FDA
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  32. EPA Chemical and Products Database (CPDat)
  33. NORMAN Suspect List Exchange
    LICENSE
    Data: CC-BY 4.0; Code (hosted by ECI, LCSB): Artistic-2.0
    https://creativecommons.org/licenses/by/4.0/
    CIMETIDINE
    NORMAN Suspect List Exchange Classification
    https://www.norman-network.com/nds/SLE/
  34. EU Clinical Trials Register
  35. FDA Orange Book
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  36. National Drug Code (NDC) Directory
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  37. USGS Health-Based Screening Levels for Evaluating Water-Quality Data
  38. SpectraBase
    2-CYANO-1-METHYL-3-{2-{[(5-METHYLIMIDAZOL-4-YL)METHYL]THIO}ETHYL}GUANIDINE
    https://spectrabase.com/spectrum/AfKZbaHjBEH
    2-cyano-1-methyl-3-{2-{[(5-methylimidazol-4-yl)methyl]thio}ethyl}guanidine
    https://spectrabase.com/spectrum/69vaH11rliR
    2-CYANO-1-METHYL-3-{2-{[(5-METHYLIMIDAZOL-4-YL)METHYL]THIO}ETHYL}GUANIDINE
    https://spectrabase.com/spectrum/I2LNYyXfH3I
    2-CYANO-1-METHYL-3-{2-{[(5-METHYLIMIDAZOL-4-YL)METHYL]THIO}ETHYL}GUANIDINE
    https://spectrabase.com/spectrum/4X2qBKNqcyZ
  39. NIST Mass Spectrometry Data Center
    LICENSE
    Data covered by the Standard Reference Data Act of 1968 as amended.
    https://www.nist.gov/srd/public-law
  40. International Agency for Research on Cancer (IARC)
    LICENSE
    Materials made available by IARC/WHO enjoy copyright protection under the Berne Convention for the Protection of Literature and Artistic Works, under other international conventions, and under national laws on copyright and neighbouring rights. IARC exercises copyright over its Materials to make sure that they are used in accordance with the Agency's principles. All rights are reserved.
    https://publications.iarc.fr/Terms-Of-Use
    IARC Classification
    https://www.iarc.fr/
  41. Japan Chemical Substance Dictionary (Nikkaji)
  42. KEGG
    LICENSE
    Academic users may freely use the KEGG website. Non-academic use of KEGG generally requires a commercial license
    https://www.kegg.jp/kegg/legal.html
    Therapeutic category of drugs in Japan
    http://www.genome.jp/kegg-bin/get_htext?br08301.keg
    Anatomical Therapeutic Chemical (ATC) classification
    http://www.genome.jp/kegg-bin/get_htext?br08303.keg
    Target-based classification of drugs
    http://www.genome.jp/kegg-bin/get_htext?br08310.keg
    Drugs listed in the Japanese Pharmacopoeia
    http://www.genome.jp/kegg-bin/get_htext?br08311.keg
    Risk category of Japanese OTC drugs
    http://www.genome.jp/kegg-bin/get_htext?br08312.keg
    Classification of Japanese OTC drugs
    http://www.genome.jp/kegg-bin/get_htext?br08313.keg
  43. MassBank Europe
  44. MassBank of North America (MoNA)
    LICENSE
    The content of the MoNA database is licensed under CC BY 4.0.
    https://mona.fiehnlab.ucdavis.edu/documentation/license
  45. Metabolomics Workbench
  46. Nature Chemical Biology
  47. NIPH Clinical Trials Search of Japan
  48. NLM RxNorm Terminology
    LICENSE
    The RxNorm Terminology is created by the National Library of Medicine (NLM) and is in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from NLM. Credit to the U.S. National Library of Medicine as the source is appreciated but not required. The full RxNorm dataset requires a free license.
    https://www.nlm.nih.gov/research/umls/rxnorm/docs/termsofservice.html
  49. PharmGKB
    LICENSE
    PharmGKB data are subject to the Creative Commons Attribution-ShareALike 4.0 license (https://creativecommons.org/licenses/by-sa/4.0/).
    https://www.pharmgkb.org/page/policies
  50. Pharos
    LICENSE
    Data accessed from Pharos and TCRD is publicly available from the primary sources listed above. Please respect their individual licenses regarding proper use and redistribution.
    https://pharos.nih.gov/about
  51. RCSB Protein Data Bank (RCSB PDB)
    LICENSE
    Data files contained in the PDB archive (ftp://ftp.wwpdb.org) are free of all copyright restrictions and made fully and freely available for both non-commercial and commercial use. Users of the data should attribute the original authors of that structural data.
    https://www.rcsb.org/pages/policies
  52. Springer Nature
  53. The Cambridge Structural Database
  54. Thieme Chemistry
    LICENSE
    The Thieme Chemistry contribution within PubChem is provided under a CC-BY-NC-ND 4.0 license, unless otherwise stated.
    https://creativecommons.org/licenses/by-nc-nd/4.0/
  55. WHO Anatomical Therapeutic Chemical (ATC) Classification
    LICENSE
    Use of all or parts of the material requires reference to the WHO Collaborating Centre for Drug Statistics Methodology. Copying and distribution for commercial purposes is not allowed. Changing or manipulating the material is not allowed.
    https://www.whocc.no/copyright_disclaimer/
  56. Wikidata
  57. Wikipedia
  58. Wiley
  59. Medical Subject Headings (MeSH)
    LICENSE
    Works produced by the U.S. government are not subject to copyright protection in the United States. Any such works found on National Library of Medicine (NLM) Web sites may be freely used or reproduced without permission in the U.S.
    https://www.nlm.nih.gov/copyright.html
    Cytochrome P-450 CYP1A2 Inhibitors
    https://www.ncbi.nlm.nih.gov/mesh/68065609
  60. PubChem
  61. GHS Classification (UNECE)
  62. EPA Substance Registry Services
  63. MolGenie
    MolGenie Organic Chemistry Ontology
    https://github.com/MolGenie/ontology/
  64. PATENTSCOPE (WIPO)
  65. NCBI
CONTENTS