Dipyridamole

Identification

Summary

Dipyridamole is a phosphodiesterase inhibitor used to prevent postoperative thromboembolic events.

Brand Names
Aggrenox, Persantine
Generic Name
Dipyridamole
DrugBank Accession Number
DB00975
Background

A phosphodiesterase inhibitor that blocks uptake and metabolism of adenosine by erythrocytes and vascular endothelial cells. Dipyridamole also potentiates the antiaggregating action of prostacyclin. (From AMA Drug Evaluations Annual, 1994, p752)

Type
Small Molecule
Groups
Approved
Structure
Weight
Average: 504.6256
Monoisotopic: 504.317251808
Chemical Formula
C24H40N8O4
Synonyms
  • Dipiridamol
  • Dipyridamine
  • Dipyridamole
  • Dipyridamolum
  • Dipyudamine
  • Dypyridamol
External IDs
  • NSC-515776
  • USAF GE-12

Pharmacology

Indication

For as an adjunct to coumarin anticoagulants in the prevention of postoperative thromboembolic complications of cardiac valve replacement and also used in prevention of angina.

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Diagnostic agentCoronary artery disease•••••••••••••••••••••• •••••••••• ••••••••
Adjunct therapy in prevention ofPostoperative thromboembolism••••••••••••
Prevention ofStroke•••••••••••••••••••• •••••••••••••
Used in combination to preventStrokeRegimen in combination with: Acetylsalicylic acid (DB00945)•••••••••••••••••••• •••••••••••••
Used in combination to preventStrokeCombination Product in combination with: Acetylsalicylic acid (DB00945)••••••••••••
Associated Therapies
Contraindications & Blackbox Warnings
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Pharmacodynamics

Dipyridamole, a non-nitrate coronary vasodilator that also inhibits platelet aggregation, is combined with other anticoagulant drugs, such as warfarin, to prevent thrombosis in patients with valvular or vascular disorders. Dipyridamole is also used in myocardial perfusion imaging, as an antiplatelet agent, and in combination with aspirin for stroke prophylaxis.

Mechanism of action

Dipyridamole likely inhibits both adenosine deaminase and phosphodiesterase, preventing the degradation of cAMP, an inhibitor of platelet function. This elevation in cAMP blocks the release of arachidonic acid from membrane phospholipids and reduces thromboxane A2 activity. Dipyridamole also directly stimulates the release of prostacyclin, which induces adenylate cyclase activity, thereby raising the intraplatelet concentration of cAMP and further inhibiting platelet aggregation.

TargetActionsOrganism
AcAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
inhibitor
Humans
AcGMP-specific 3',5'-cyclic phosphodiesterase
inhibitor
Humans
A3',5'-cyclic-AMP phosphodiesterase 4A
inhibitor
Humans
AAdenosine deaminase
inhibitor
Humans
UCalcipressin-1Not AvailableHumans
UAlpha-1-acid glycoprotein 1Not AvailableHumans
Absorption

70%

Volume of distribution
  • 1 to 2.5 L/kg
Protein binding

99%

Metabolism

hepatic

Route of elimination

Dipyridamole is metabolized in the liver to the glucuronic acid conjugate and excreted with the bile.

Half-life

40 minutes

Clearance
  • 2.3-3.5 mL/min/kg
Adverse Effects
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Toxicity

Hypotension, if it occurs, is likely to be of short duration, but a vasopressor drug may be used if necessary. The oral LD50 in rats is greater than 6,000 mg/kg while in the dogs, the oral LD50 is approximately 400 mg/kg. LD50=8.4g/kg (orally in rat)

Pathways
PathwayCategory
Dipyridamole (Antiplatelet) Action PathwayDrug action
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbaloparatideThe risk or severity of adverse effects can be increased when Dipyridamole is combined with Abaloparatide.
AbciximabThe risk or severity of bleeding can be increased when Abciximab is combined with Dipyridamole.
AbrocitinibThe risk or severity of bleeding and thrombocytopenia can be increased when Dipyridamole is combined with Abrocitinib.
AcebutololDipyridamole may increase the bradycardic activities of Acebutolol.
AceclofenacThe risk or severity of bleeding and hemorrhage can be increased when Aceclofenac is combined with Dipyridamole.
Food Interactions
  • Avoid herbs and supplements with anticoagulant/antiplatelet activity. Examples include garlic, ginger, bilberry, danshen, piracetam, and ginkgo biloba.
  • Avoid xanthines. Xanthines, found in coffee and tea, can reduce the effectiveness of this medication.
  • Take with or without food. Taking dipyridamole extrended release capusels with a high-fat meal minimally reduces it's AUC and Cmax.

Products

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Product Images
International/Other Brands
Agilease (lsei) / Cardoxin (Rafa) / Cleridium 150 (Millot) / Curantyl (Arzneimittelwerk) / Persantin
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
DipyridamoleInjection, solution5 mg/1mLIntravenousHospira, Inc.2006-04-07Not applicableUS flag
DipyridamoleSolution5 mg/1mLIntravenousAnazao Health Corporation2012-05-23Not applicableUS flag
DipyridamoleInjection, solution5 mg/1mLIntravenousHospira, Inc.2006-04-07Not applicableUS flag
Dipyridamole 25 Tab 25mgTablet25 mgOralPro Doc Limitee1983-12-312002-08-02Canada flag
Dipyridamole 50 Tab 50mgTablet50 mgOralPro Doc Limitee1983-12-312002-08-02Canada flag
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Apo-dipyridamoleTablet100 mgOralApotex CorporationNot applicableNot applicableCanada flag
Apo-dipyridamoleTablet75 mgOralApotex Corporation1990-12-31Not applicableCanada flag
Apo-dipyridamoleTablet50 mgOralApotex Corporation1990-12-31Not applicableCanada flag
Apo-dipyridamoleTablet25 mgOralApotex Corporation1990-12-31Not applicableCanada flag
Apo-dipyridamole-SC Tab 25mgTablet25 mgOralApotex Corporation1982-12-31Not applicableCanada flag
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
AggrenoxDipyridamole (200 mg/1) + Acetylsalicylic acid (25 mg/1)CapsuleOralRebel Distributors1999-12-19Not applicableUS flag
AggrenoxDipyridamole (200 mg/1) + Acetylsalicylic acid (25 mg/1)Capsule, extended releaseOralBoehringer Ingelheim Pharmaceuticals, Inc.1999-12-19Not applicableUS flag
AGGRENOXDipyridamole (200 MG) + Acetylsalicylic acid (25 MG)CapsuleOralBoehringer Ingelheim2014-07-082016-06-12Italy flag
AggrenoxDipyridamole (200 mg/1) + Acetylsalicylic acid (25 mg/1)Capsule, extended releaseOralCarilion Materials Management1999-12-19Not applicableUS flag
AGGRENOXDipyridamole (200 MG) + Acetylsalicylic acid (25 MG)CapsuleOralBoehringer Ingelheim2014-07-082021-05-07Italy flag
Unapproved/Other Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
DipyridamoleDipyridamole (5 mg/1mL)SolutionIntravenousAnazao Health Corporation2012-05-23Not applicableUS flag

Categories

ATC Codes
B01AC07 — Dipyridamole
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as dialkylarylamines. These are aliphatic aromatic amines in which the amino group is linked to two aliphatic chains and one aromatic group.
Kingdom
Organic compounds
Super Class
Organic nitrogen compounds
Class
Organonitrogen compounds
Sub Class
Amines
Direct Parent
Dialkylarylamines
Alternative Parents
Aminopyrimidines and derivatives / Piperidines / Imidolactams / Heteroaromatic compounds / Azacyclic compounds / Alkanolamines / Primary alcohols / Organopnictogen compounds / Hydrocarbon derivatives
Substituents
Alcohol / Alkanolamine / Aminopyrimidine / Aromatic heteropolycyclic compound / Azacycle / Dialkylarylamine / Heteroaromatic compound / Hydrocarbon derivative / Imidolactam / Organic oxygen compound
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
piperidines, tertiary amino compound, tetrol, pyrimidopyrimidine (CHEBI:4653)
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
64ALC7F90C
CAS number
58-32-2
InChI Key
IZEKFCXSFNUWAM-UHFFFAOYSA-N
InChI
InChI=1S/C24H40N8O4/c33-15-11-31(12-16-34)23-26-20-19(21(27-23)29-7-3-1-4-8-29)25-24(32(13-17-35)14-18-36)28-22(20)30-9-5-2-6-10-30/h33-36H,1-18H2
IUPAC Name
2-({6-[bis(2-hydroxyethyl)amino]-4,8-bis(piperidin-1-yl)-[1,3]diazino[5,4-d]pyrimidin-2-yl}(2-hydroxyethyl)amino)ethan-1-ol
SMILES
OCCN(CCO)C1=NC2=C(N=C(N=C2N2CCCCC2)N(CCO)CCO)C(=N1)N1CCCCC1

References

Synthesis Reference

Minutza Leibovici, Itamar Kanari, Michael Fox, "Dipyridamole extended-release formulations and process for preparing same." U.S. Patent US20070184110, issued August 09, 2007.

US20070184110
General References
  1. Diener HC, Cunha L, Forbes C, Sivenius J, Smets P, Lowenthal A: European Stroke Prevention Study. 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci. 1996 Nov;143(1-2):1-13. [Article]
Human Metabolome Database
HMDB0015110
KEGG Drug
D00302
PubChem Compound
3108
PubChem Substance
46506292
ChemSpider
2997
BindingDB
23620
RxNav
3521
ChEBI
4653
ChEMBL
CHEMBL932
ZINC
ZINC000000643046
Therapeutic Targets Database
DNC001625
PharmGKB
PA449367
PDBe Ligand
H9F
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Dipyridamole
PDB Entries
7dmc / 8i4a / 8t6u
FDA label
Download (48.7 KB)
MSDS
Download (73.3 KB)

Clinical Trials

Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package
PhaseStatusPurposeConditionsCountStart DateWhy Stopped100+ additional columns
Not AvailableCompletedNot AvailableAtherosclerosis / Cardiovascular Disease (CVD) / Stenosis, Carotid / Stroke1somestatusstop reasonjust information to hide
Not AvailableCompletedBasic ScienceHyperemia / Hypoxia1somestatusstop reasonjust information to hide
Not AvailableCompletedPreventionCirrhosis of the Liver / Portal Hypertension / Splenectomy / Venous Thrombosis (Disorder)1somestatusstop reasonjust information to hide
Not AvailableCompletedTreatmentSchizoaffective Disorders / Schizophrenia / Schizophreniform Disorders1somestatusstop reasonjust information to hide
Not AvailableCompletedTreatmentStroke / Transient Ischemic Attack1somestatusstop reasonjust information to hide

Pharmacoeconomics

Manufacturers
  • App pharmaceuticals llc
  • Baxter healthcare corp anesthesia and critical care
  • Bedford laboratories div ben venue laboratories inc
  • Claris lifesciences ltd
  • Hospira inc
  • Teva parenteral medicines inc
  • Boehringer ingelheim pharmaceuticals inc
  • Actavis totowa llc
  • Barr laboratories inc
  • Glenmark generics inc usa
  • Impax laboratories inc
  • Lannett holdings inc
  • Murty pharmaceuticals inc
  • Purepac pharmaceutical co
  • Sandoz inc
  • Watson laboratories inc
  • Zydus pharmaceuticals usa inc
  • Boehringer Ingelheim Pharmaceuticals, Inc
Packagers
  • Amerisource Health Services Corp.
  • Apotex Inc.
  • APP Pharmaceuticals
  • Avkare Incorporated
  • Barr Pharmaceuticals
  • Baxter International Inc.
  • Bedford Labs
  • Ben Venue Laboratories Inc.
  • Boehringer Ingelheim Ltd.
  • Cadila Healthcare Ltd.
  • Cardinal Health
  • Direct Dispensing Inc.
  • Dispensing Solutions
  • General Injectables and Vaccines Inc.
  • Glenmark Generics Ltd.
  • Global Pharmaceuticals
  • Group Health Cooperative
  • H and H Laboratories
  • Heartland Repack Services LLC
  • Hospira Inc.
  • Impax Laboratories Inc.
  • Kaiser Foundation Hospital
  • Lake Erie Medical and Surgical Supply
  • Lannett Co. Inc.
  • Major Pharmaceuticals
  • Mallinckrodt Inc.
  • Mead Johnson and Co.
  • Murfreesboro Pharmaceutical Nursing Supply
  • Murty Pharmaceuticals Inc.
  • Novex Pharma
  • PCA LLC
  • PD-Rx Pharmaceuticals Inc.
  • Pharmaceutical Utilization Management Program VA Inc.
  • Physicians Total Care Inc.
  • Prepak Systems Inc.
  • Qualitest
  • Rebel Distributors Corp.
  • Resource Optimization and Innovation LLC
  • Rising Pharmaceuticals
  • Sandhills Packaging Inc.
  • Sicor Pharmaceuticals
  • Southwood Pharmaceuticals
  • Spectrum Pharmaceuticals
  • Teva Pharmaceutical Industries Ltd.
  • UDL Laboratories
  • Vangard Labs Inc.
  • Zydus Pharmaceuticals
Dosage Forms
FormRouteStrength
CapsuleOral
CapsuleOral25.000 MG
Capsule, extended releaseOral
TabletOral50 mg
Capsule, delayed releaseOral
TabletOral
Tablet, coatedOral100 mg
InjectionIntravenous5 mg/1mL
Injection, solutionIntravenous5 mg/1mL
SolutionIntravenous5 mg/1mL
TabletOral25 mg/1
TabletOral50 mg/1
TabletOral75 mg/1
Tablet, film coatedOral25 mg/1
Tablet, film coatedOral50 mg/1
Tablet, film coatedOral75 mg/1
LiquidIntravenous5 mg / mL
SolutionParenteral5 mg
Tablet, delayed releaseOral
TabletOral100 mg
Pill
Tablet, sugar coatedOral25 mg
Tablet, sugar coatedOral75 mg
Capsule200 MG
Injection, solutionIntravenous10 MG/2ML
Pill75 MG
SolutionParenteral10.000 mg
TabletOral75.000 mg
Tablet, coatedOral
SolutionIntravenous10 mg
SolutionIntravenous; Parenteral10 mg
Tablet, delayed releaseOral75 mg
InjectionIntramuscular; Intravenous10 mg/2ml
SolutionIntravenous5 mg / mL
Tablet, coatedOral25 mg/1
Tablet, coatedOral50 mg/1
Tablet, coatedOral75 mg/1
TabletOral25 mg
TabletOral75 mg
Tablet, film coatedOral75 mg
Tablet, coatedOral75 mg
Tablet, coatedOral25 mg
Prices
Unit descriptionCostUnit
Dipyridamole powder5.34USD g
Aggrenox capsule sa3.25USD capsule
Aggrenox 25-200 mg 12 Hour Capsule3.0USD capsule
Dipyridamole 5 mg/ml ampul1.5USD ml
Persantine 75 mg tablet1.46USD tablet
Dipyridamole 5 mg/ml vial1.32USD ml
Dipyridamole 75 mg tablet1.28USD tablet
Persantine 50 mg tablet1.09USD tablet
Dipyridamole 50 mg tablet0.96USD tablet
Persantine 25 mg tablet0.89USD tablet
Dipyridamole 25 mg tablet0.58USD tablet
Apo-Dipyridamole (Fc) 75 mg Tablet0.46USD tablet
Apo-Dipyridamole (Fc) 50 mg Tablet0.31USD tablet
Apo-Dipyridamole (Fc) 25 mg Tablet0.28USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US6015577No2000-01-182017-01-18US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)163 °CPhysProp
water solubilitySlightlyNot Available
logP1.5Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.922 mg/mLALOGPS
logP1.52ALOGPS
logP1.81Chemaxon
logS-2.7ALOGPS
pKa (Strongest Acidic)14.97Chemaxon
pKa (Strongest Basic)3.54Chemaxon
Physiological Charge0Chemaxon
Hydrogen Acceptor Count12Chemaxon
Hydrogen Donor Count4Chemaxon
Polar Surface Area145.44 Å2Chemaxon
Rotatable Bond Count12Chemaxon
Refractivity142.78 m3·mol-1Chemaxon
Polarizability56.93 Å3Chemaxon
Number of Rings4Chemaxon
Bioavailability0Chemaxon
Rule of FiveNoChemaxon
Ghose FilterNoChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleYesChemaxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.9917
Blood Brain Barrier-0.6246
Caco-2 permeable-0.7261
P-glycoprotein substrateSubstrate0.7696
P-glycoprotein inhibitor INon-inhibitor0.5321
P-glycoprotein inhibitor IINon-inhibitor0.8383
Renal organic cation transporterNon-inhibitor0.615
CYP450 2C9 substrateNon-substrate0.8345
CYP450 2D6 substrateNon-substrate0.6825
CYP450 3A4 substrateNon-substrate0.6849
CYP450 1A2 substrateNon-inhibitor0.9045
CYP450 2C9 inhibitorInhibitor0.8045
CYP450 2D6 inhibitorInhibitor0.7201
CYP450 2C19 inhibitorNon-inhibitor0.957
CYP450 3A4 inhibitorInhibitor0.6789
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.7806
Ames testNon AMES toxic0.7009
CarcinogenicityNon-carcinogens0.8884
BiodegradationNot ready biodegradable0.988
Rat acute toxicity2.1167 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Strong inhibitor0.5271
hERG inhibition (predictor II)Non-inhibitor0.633
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSsplash10-00di-1013900000-667f6d46e6523b3a3d7a
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSsplash10-0udl-0291000000-caeb14eb3ea863e020a0
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSsplash10-0udl-0291000000-2fc7956fe6ea13c73317
MS/MS Spectrum - , positiveLC-MS/MSsplash10-0udl-0291000000-2fc7956fe6ea13c73317
MS/MS Spectrum - , positiveLC-MS/MSsplash10-0a4i-0001190000-346cf73a19cbefa2dc11
MS/MS Spectrum - , positiveLC-MS/MSsplash10-0a4i-0013490000-839580758bc83767be8f
MS/MS Spectrum - , positiveLC-MS/MSsplash10-0udl-0291000000-caeb14eb3ea863e020a0
MS/MS Spectrum - , positiveLC-MS/MSsplash10-0a4i-1348890000-aa1e3a113b8c2768cb08
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-0a4i-0000190000-4d24cdca3afcfa3f1919
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-0udr-0000970000-e95bbde87e834f542c3e
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-0bt9-0000890000-173b3950a6d006ca4c53
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-066u-0000900000-1868ae2da956078a47b8
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-0006-0000900000-5729d96eaae363749107
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-0a4l-0001900000-46707fa699697d415d38
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-236.8521267
predicted
DarkChem Lite v0.1.0
[M-H]-236.6562267
predicted
DarkChem Lite v0.1.0
[M-H]-219.1389
predicted
DeepCCS 1.0 (2019)
[M+H]+235.7354267
predicted
DarkChem Lite v0.1.0
[M+H]+235.8137267
predicted
DarkChem Lite v0.1.0
[M+H]+221.4969
predicted
DeepCCS 1.0 (2019)
[M+Na]+235.6288267
predicted
DarkChem Lite v0.1.0
[M+Na]+235.5341267
predicted
DarkChem Lite v0.1.0
[M+Na]+227.79008
predicted
DeepCCS 1.0 (2019)

Targets

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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Plays a role in signal transduction by regulating the intracellular concentration of cyclic nucleotides (PubMed:10373451, PubMed:10393245, PubMed:16330539, PubMed:17389385, PubMed:27058447). Can hydrolyze both cAMP and cGMP, but has higher affinity for cAMP and is more efficient with cAMP as substrate (PubMed:10373451, PubMed:10393245, PubMed:17389385, PubMed:27058447). May play a critical role in regulating cAMP and cGMP levels in the striatum, a region of the brain that contributes to the control of movement and cognition (PubMed:27058447)
Specific Function
3',5'-cyclic-AMP phosphodiesterase activity
Gene Name
PDE10A
Uniprot ID
Q9Y233
Uniprot Name
cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
Molecular Weight
114945.16 Da
References
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [Article]
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [Article]
  3. Fujishige K, Kotera J, Michibata H, Yuasa K, Takebayashi S, Okumura K, Omori K: Cloning and characterization of a novel human phosphodiesterase that hydrolyzes both cAMP and cGMP (PDE10A). J Biol Chem. 1999 Jun 25;274(26):18438-45. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Plays a role in signal transduction by regulating the intracellular concentration of cyclic nucleotides. This phosphodiesterase catalyzes the specific hydrolysis of cGMP to 5'-GMP (PubMed:15489334, PubMed:9714779). Specifically regulates nitric-oxide-generated cGMP (PubMed:15489334)
Specific Function
3',5'-cyclic-AMP phosphodiesterase activity
Gene Name
PDE5A
Uniprot ID
O76074
Uniprot Name
cGMP-specific 3',5'-cyclic phosphodiesterase
Molecular Weight
99984.14 Da
References
  1. Kulkarni SK, Patil CS: Phosphodiesterase 5 enzyme and its inhibitors: update on pharmacological and therapeutical aspects. Methods Find Exp Clin Pharmacol. 2004 Dec;26(10):789-99. [Article]
  2. Santini F, Casali G, Franchi G, Auriemma S, Lusini M, Barozzi L, Favaro A, Messina A, Mazzucco A: Hemodynamic effects of inhaled nitric oxide and phosphodiesterase inhibitor (dipyridamole) on secondary pulmonary hypertension following heart valve surgery in adults. Int J Cardiol. 2005 Aug 18;103(2):156-63. [Article]
  3. Kruuse C, Lassen LH, Iversen HK, Oestergaard S, Olesen J: Dipyridamole may induce migraine in patients with migraine without aura. Cephalalgia. 2006 Aug;26(8):925-33. [Article]
  4. Jackson EK, Ren J, Zacharia LC, Mi Z: Characterization of renal ecto-phosphodiesterase. J Pharmacol Exp Ther. 2007 May;321(2):810-5. Epub 2007 Feb 16. [Article]
  5. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Hydrolyzes the second messenger 3',5'-cyclic AMP (cAMP), which is a key regulator of many important physiological processes
Specific Function
3',5'-cyclic-AMP phosphodiesterase activity
Gene Name
PDE4A
Uniprot ID
P27815
Uniprot Name
3',5'-cyclic-AMP phosphodiesterase 4A
Molecular Weight
98142.155 Da
References
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Catalyzes the hydrolytic deamination of adenosine and 2-deoxyadenosine (PubMed:16670267, PubMed:23193172, PubMed:26166670, PubMed:8452534, PubMed:9361033). Plays an important role in purine metabolism and in adenosine homeostasis. Modulates signaling by extracellular adenosine, and so contributes indirectly to cellular signaling events. Acts as a positive regulator of T-cell coactivation, by binding DPP4 (PubMed:20959412). Its interaction with DPP4 regulates lymphocyte-epithelial cell adhesion (PubMed:11772392). Enhances dendritic cell immunogenicity by affecting dendritic cell costimulatory molecule expression and cytokines and chemokines secretion (By similarity). Enhances CD4+ T-cell differentiation and proliferation (PubMed:20959412). Acts as a positive modulator of adenosine receptors ADORA1 and ADORA2A, by enhancing their ligand affinity via conformational change (PubMed:23193172). Stimulates plasminogen activation (PubMed:15016824). Plays a role in male fertility (PubMed:21919946, PubMed:26166670). Plays a protective role in early postimplantation embryonic development (By similarity). Also responsible for the deamination of cordycepin (3'-deoxyadenosine), a fungal natural product that shows antitumor, antibacterial, antifungal, antivirus, and immune regulation properties (PubMed:26038697)
Specific Function
2'-deoxyadenosine deaminase activity
Gene Name
ADA
Uniprot ID
P00813
Uniprot Name
Adenosine deaminase
Molecular Weight
40764.13 Da
References
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Inhibits calcineurin-dependent transcriptional responses by binding to the catalytic domain of calcineurin A (PubMed:12809556). Could play a role during central nervous system development (By similarity)
Specific Function
calcium-dependent protein serine/threonine phosphatase regulator activity
Gene Name
RCAN1
Uniprot ID
P53805
Uniprot Name
Calcipressin-1
Molecular Weight
28078.425 Da
References
  1. Mulero MC, Aubareda A, Orzaez M, Messeguer J, Serrano-Candelas E, Martinez-Hoyer S, Messeguer A, Perez-Paya E, Perez-Riba M: Inhibiting the calcineurin-NFAT (nuclear factor of activated T cells) signaling pathway with a regulator of calcineurin-derived peptide without affecting general calcineurin phosphatase activity. J Biol Chem. 2009 Apr 3;284(14):9394-401. doi: 10.1074/jbc.M805889200. Epub 2009 Feb 3. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Functions as a transport protein in the blood stream. Binds various ligands in the interior of its beta-barrel domain. Also binds synthetic drugs and influences their distribution and availability in the body. Appears to function in modulating the activity of the immune system during the acute-phase reaction
Specific Function
Not Available
Gene Name
ORM1
Uniprot ID
P02763
Uniprot Name
Alpha-1-acid glycoprotein 1
Molecular Weight
23539.43 Da
References
  1. Herve F, Duche JC, d'Athis P, Marche C, Barre J, Tillement JP: Binding of disopyramide, methadone, dipyridamole, chlorpromazine, lignocaine and progesterone to the two main genetic variants of human alpha 1-acid glycoprotein: evidence for drug-binding differences between the variants and for the presence of two separate drug-binding sites on alpha 1-acid glycoprotein. Pharmacogenetics. 1996 Oct;6(5):403-15. [Article]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
ATP-dependent transporter of the ATP-binding cassette (ABC) family that actively extrudes physiological compounds and xenobiotics from cells. Transports a range of endogenous molecules that have a key role in cellular communication and signaling, including cyclic nucleotides such as cyclic AMP (cAMP) and cyclic GMP (cGMP), bile acids, steroid conjugates, urate, and prostaglandins (PubMed:11856762, PubMed:12523936, PubMed:12835412, PubMed:12883481, PubMed:15364914, PubMed:15454390, PubMed:16282361, PubMed:17959747, PubMed:18300232, PubMed:26721430). Mediates the ATP-dependent efflux of glutathione conjugates such as leukotriene C4 (LTC4) and leukotriene B4 (LTB4) too. The presence of GSH is necessary for the ATP-dependent transport of LTB4, whereas GSH is not required for the transport of LTC4 (PubMed:17959747). Mediates the cotransport of bile acids with reduced glutathione (GSH) (PubMed:12523936, PubMed:12883481, PubMed:16282361). Transports a wide range of drugs and their metabolites, including anticancer, antiviral and antibiotics molecules (PubMed:11856762, PubMed:12105214, PubMed:15454390, PubMed:17344354, PubMed:18300232). Confers resistance to anticancer agents such as methotrexate (PubMed:11106685)
Specific Function
15-hydroxyprostaglandin dehydrogenase (NAD+) activity
Gene Name
ABCC4
Uniprot ID
O15439
Uniprot Name
ATP-binding cassette sub-family C member 4
Molecular Weight
149525.33 Da
References
  1. van Aubel RA, Smeets PH, Peters JG, Bindels RJ, Russel FG: The MRP4/ABCC4 gene encodes a novel apical organic anion transporter in human kidney proximal tubules: putative efflux pump for urinary cAMP and cGMP. J Am Soc Nephrol. 2002 Mar;13(3):595-603. [Article]
  2. Reid G, Wielinga P, Zelcer N, De Haas M, Van Deemter L, Wijnholds J, Balzarini J, Borst P: Characterization of the transport of nucleoside analog drugs by the human multidrug resistance proteins MRP4 and MRP5. Mol Pharmacol. 2003 May;63(5):1094-103. [Article]
  3. Rius M, Nies AT, Hummel-Eisenbeiss J, Jedlitschky G, Keppler D: Cotransport of reduced glutathione with bile salts by MRP4 (ABCC4) localized to the basolateral hepatocyte membrane. Hepatology. 2003 Aug;38(2):374-84. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
ATP-dependent transporter of the ATP-binding cassette (ABC) family that actively extrudes physiological compounds, and xenobiotics from cells. Mediates ATP-dependent transport of endogenous metabolites such as cAMP and cGMP, folic acid and N-lactoyl-amino acids (in vitro) (PubMed:10893247, PubMed:12637526, PubMed:12695538, PubMed:15899835, PubMed:17229149, PubMed:25964343). Acts also as a general glutamate conjugate and analog transporter that can limit the brain levels of endogenous metabolites, drugs, and toxins (PubMed:26515061). Confers resistance to the antiviral agent PMEA (PubMed:12695538). Able to transport several anticancer drugs including methotrexate, and nucleotide analogs in vitro, however it does with low affinity, thus the exact role of ABCC5 in mediating resistance still needs to be elucidated (PubMed:10840050, PubMed:12435799, PubMed:12695538, PubMed:15899835). Acts as a heme transporter required for the translocation of cytosolic heme to the secretory pathway (PubMed:24836561). May play a role in energy metabolism by regulating the glucagon-like peptide 1 (GLP-1) secretion from enteroendocrine cells (By similarity)
Specific Function
ABC-type xenobiotic transporter activity
Gene Name
ABCC5
Uniprot ID
O15440
Uniprot Name
ATP-binding cassette sub-family C member 5
Molecular Weight
160658.8 Da
References
  1. Reid G, Wielinga P, Zelcer N, De Haas M, Van Deemter L, Wijnholds J, Balzarini J, Borst P: Characterization of the transport of nucleoside analog drugs by the human multidrug resistance proteins MRP4 and MRP5. Mol Pharmacol. 2003 May;63(5):1094-103. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Translocates drugs and phospholipids across the membrane (PubMed:2897240, PubMed:35970996, PubMed:8898203, PubMed:9038218). Catalyzes the flop of phospholipids from the cytoplasmic to the exoplasmic leaflet of the apical membrane. Participates mainly to the flop of phosphatidylcholine, phosphatidylethanolamine, beta-D-glucosylceramides and sphingomyelins (PubMed:8898203). Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells (PubMed:2897240, PubMed:35970996, PubMed:9038218)
Specific Function
ABC-type xenobiotic transporter activity
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
ATP-dependent translocase ABCB1
Molecular Weight
141477.255 Da
References
  1. Polli JW, Wring SA, Humphreys JE, Huang L, Morgan JB, Webster LO, Serabjit-Singh CS: Rational use of in vitro P-glycoprotein assays in drug discovery. J Pharmacol Exp Ther. 2001 Nov;299(2):620-8. [Article]
  2. Wang EJ, Casciano CN, Clement RP, Johnson WW: Active transport of fluorescent P-glycoprotein substrates: evaluation as markers and interaction with inhibitors. Biochem Biophys Res Commun. 2001 Nov 30;289(2):580-5. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Mediates the Na(+)-independent uptake of organic anions (PubMed:10358072, PubMed:15159445, PubMed:17412826). Shows broad substrate specificity, can transport both organic anions such as bile acid taurocholate (cholyltaurine) and conjugated steroids (dehydroepiandrosterone 3-sulfate, 17-beta-glucuronosyl estradiol, and estrone 3-sulfate), as well as eicosanoids (prostaglandin E2, thromboxane B2, leukotriene C4, and leukotriene E4), and thyroid hormones (T4/L-thyroxine, and T3/3,3',5'-triiodo-L-thyronine) (PubMed:10358072, PubMed:10601278, PubMed:10873595, PubMed:11159893, PubMed:12196548, PubMed:12568656, PubMed:15159445, PubMed:15970799, PubMed:16627748, PubMed:17412826, PubMed:19129463, PubMed:26979622). Can take up bilirubin glucuronides from plasma into the liver, contributing to the detoxification-enhancing liver-blood shuttling loop (PubMed:22232210). Involved in the clearance of endogenous and exogenous substrates from the liver (PubMed:10358072, PubMed:10601278). Transports coproporphyrin I and III, by-products of heme synthesis, and may be involved in their hepatic disposition (PubMed:26383540). May contribute to regulate the transport of organic compounds in testes across the blood-testis-barrier (Probable). Can transport HMG-CoA reductase inhibitors (also known as statins), such as pravastatin and pitavastatin, a clinically important class of hypolipidemic drugs (PubMed:10601278, PubMed:15159445, PubMed:15970799). May play an important role in plasma and tissue distribution of the structurally diverse chemotherapeutic drug methotrexate (PubMed:23243220). May also transport antihypertension agents, such as the angiotensin-converting enzyme (ACE) inhibitor prodrug enalapril, and the highly selective angiotensin II AT1-receptor antagonist valsartan, in the liver (PubMed:16624871, PubMed:16627748). Shows a pH-sensitive substrate specificity towards prostaglandin E2 and T4 which may be ascribed to the protonation state of the binding site and leads to a stimulation of substrate transport in an acidic microenvironment (PubMed:19129463). Hydrogencarbonate/HCO3(-) acts as the probable counteranion that exchanges for organic anions (PubMed:19129463)
Specific Function
bile acid transmembrane transporter activity
Gene Name
SLCO1B1
Uniprot ID
Q9Y6L6
Uniprot Name
Solute carrier organic anion transporter family member 1B1
Molecular Weight
76447.99 Da
References
  1. Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P: Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions. J Med Chem. 2012 May 24;55(10):4740-63. doi: 10.1021/jm300212s. Epub 2012 May 15. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Mediates the Na(+)-independent uptake of organic anions (PubMed:10779507, PubMed:15159445, PubMed:17412826). Shows broad substrate specificity, can transport both organic anions such as bile acid taurocholate (cholyltaurine) and conjugated steroids (17-beta-glucuronosyl estradiol, dehydroepiandrosterone sulfate (DHEAS), and estrone 3-sulfate), as well as eicosanoid leukotriene C4, prostaglandin E2 and L-thyroxine (T4) (PubMed:10779507, PubMed:11159893, PubMed:12568656, PubMed:15159445, PubMed:17412826, PubMed:19129463). Hydrogencarbonate/HCO3(-) acts as the probable counteranion that exchanges for organic anions (PubMed:19129463). Shows a pH-sensitive substrate specificity towards sulfated steroids, taurocholate and T4 which may be ascribed to the protonation state of the binding site and leads to a stimulation of substrate transport in an acidic microenvironment (PubMed:19129463). Involved in the clearance of bile acids and organic anions from the liver (PubMed:22232210). Can take up bilirubin glucuronides from plasma into the liver, contributing to the detoxification-enhancing liver-blood shuttling loop (PubMed:22232210). Transports coproporphyrin I and III, by-products of heme synthesis, and may be involved in their hepatic disposition (PubMed:26383540). May contribute to regulate the transport of organic compounds in testes across the blood-testis-barrier (Probable). Can transport HMG-CoA reductase inhibitors (also known as statins) such as pitavastatin, a clinically important class of hypolipidemic drugs (PubMed:15159445). May play an important role in plasma and tissue distribution of the structurally diverse chemotherapeutic drugs methotrexate and paclitaxel (PubMed:23243220). May also transport antihypertension agents, such as the angiotensin-converting enzyme (ACE) inhibitor prodrug enalapril, and the highly selective angiotensin II AT1-receptor antagonist valsartan, in the liver (PubMed:16624871, PubMed:16627748)
Specific Function
bile acid transmembrane transporter activity
Gene Name
SLCO1B3
Uniprot ID
Q9NPD5
Uniprot Name
Solute carrier organic anion transporter family member 1B3
Molecular Weight
77402.175 Da
References
  1. Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P: Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions. J Med Chem. 2012 May 24;55(10):4740-63. doi: 10.1021/jm300212s. Epub 2012 May 15. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Mediates the Na(+)-independent transport of steroid sulfate conjugates and other specific organic anions (PubMed:10873595, PubMed:11159893, PubMed:11932330, PubMed:12724351, PubMed:14610227, PubMed:16908597, PubMed:18501590, PubMed:20507927, PubMed:22201122, PubMed:23531488, PubMed:25132355, PubMed:26383540, PubMed:27576593, PubMed:28408210, PubMed:29871943, PubMed:34628357). Responsible for the transport of estrone 3-sulfate (E1S) through the basal membrane of syncytiotrophoblast, highlighting a potential role in the placental absorption of fetal-derived sulfated steroids including the steroid hormone precursor dehydroepiandrosterone sulfate (DHEA-S) (PubMed:11932330, PubMed:12409283). Also facilitates the uptake of sulfated steroids at the basal/sinusoidal membrane of hepatocytes, therefore accounting for the major part of organic anions clearance of liver (PubMed:11159893). Mediates the intestinal uptake of sulfated steroids (PubMed:12724351, PubMed:28408210). Mediates the uptake of the neurosteroids DHEA-S and pregnenolone sulfate (PregS) into the endothelial cells of the blood-brain barrier as the first step to enter the brain (PubMed:16908597, PubMed:25132355). Also plays a role in the reuptake of neuropeptides such as substance P/TAC1 and vasoactive intestinal peptide/VIP released from retinal neurons (PubMed:25132355). May act as a heme transporter that promotes cellular iron availability via heme oxygenase/HMOX2 and independently of TFRC (PubMed:35714613). Also transports heme by-product coproporphyrin III (CPIII), and may be involved in their hepatic disposition (PubMed:26383540). Mediates the uptake of other substrates such as prostaglandins D2 (PGD2), E1 (PGE1) and E2 (PGE2), taurocholate, L-thyroxine, leukotriene C4 and thromboxane B2 (PubMed:10873595, PubMed:14610227, PubMed:19129463, PubMed:29871943, Ref.25). May contribute to regulate the transport of organic compounds in testis across the blood-testis-barrier (Probable). Shows a pH-sensitive substrate specificity which may be ascribed to the protonation state of the binding site and leads to a stimulation of substrate transport in an acidic microenvironment (PubMed:14610227, PubMed:19129463, PubMed:22201122). The exact transport mechanism has not been yet deciphered but most likely involves an anion exchange, coupling the cellular uptake of organic substrate with the efflux of an anionic compound (PubMed:19129463, PubMed:20507927, PubMed:26277985). Hydrogencarbonate/HCO3(-) acts as a probable counteranion that exchanges for organic anions (PubMed:19129463). Cytoplasmic glutamate may also act as counteranion in the placenta (PubMed:26277985). An inwardly directed proton gradient has also been proposed as the driving force of E1S uptake with a (H(+):E1S) stoichiometry of (1:1) (PubMed:20507927)
Specific Function
bile acid transmembrane transporter activity
Gene Name
SLCO2B1
Uniprot ID
O94956
Uniprot Name
Solute carrier organic anion transporter family member 2B1
Molecular Weight
76697.93 Da
References
  1. Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P: Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions. J Med Chem. 2012 May 24;55(10):4740-63. doi: 10.1021/jm300212s. Epub 2012 May 15. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Catalyzes the transport of the major hydrophobic bile salts, such as taurine and glycine-conjugated cholic acid across the canalicular membrane of hepatocytes in an ATP-dependent manner, therefore participates in hepatic bile acid homeostasis and consequently to lipid homeostasis through regulation of biliary lipid secretion in a bile salts dependent manner (PubMed:15791618, PubMed:16332456, PubMed:18985798, PubMed:19228692, PubMed:20010382, PubMed:20398791, PubMed:22262466, PubMed:24711118, PubMed:29507376, PubMed:32203132). Transports taurine-conjugated bile salts more rapidly than glycine-conjugated bile salts (PubMed:16332456). Also transports non-bile acid compounds, such as pravastatin and fexofenadine in an ATP-dependent manner and may be involved in their biliary excretion (PubMed:15901796, PubMed:18245269)
Specific Function
ABC-type bile acid transporter activity
Gene Name
ABCB11
Uniprot ID
O95342
Uniprot Name
Bile salt export pump
Molecular Weight
146405.83 Da
References
  1. Pedersen JM, Matsson P, Bergstrom CA, Hoogstraate J, Noren A, LeCluyse EL, Artursson P: Early identification of clinically relevant drug interactions with the human bile salt export pump (BSEP/ABCB11). Toxicol Sci. 2013 Dec;136(2):328-43. doi: 10.1093/toxsci/kft197. Epub 2013 Sep 6. [Article]

Drug created at June 13, 2005 13:24 / Updated at November 03, 2024 19:35