PDE/phosphodiesterase

In OCI-AML-3 cells, dipyridamole (5 μM; 15 min) increased intracellular cAMP levels 2.5-fold [2]. Primary AML cells undergo apoptosis when statins and dipyridamole (5 μM; 48 hours) are combined [2]. Dipyridamole (5 μM; 48 hours) inhibits statin-induced SREBP2 activation in a cAMP/PKA-independent manner [2].

Dipyridamole (10 mg/kg); taken orally, once daily for eighteen days) inhibits the growth of tumors, enhances blood flow while simultaneously altering the tumor's tissue, and increases platelet infiltration [3].

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In a tumor-bearing model established using murine Lewis lung carcinoma (LLC) cells and C57BL/6 mice, the tumor suppressive effect of dipyridamole correlated well with decreased circulating white blood cells, soluble P-selectin, TGF-β1 (Transforming Growth Factor-β1), exosomes, and exosomal HMGB1, as well as tumor platelet infiltration. Exosome release inhibitor GW4869 exhibited suppressive effects as well. The suppressive effect of dipyridamole on cancer cell survival was paralleled by a reduction of HMGB1/receptor for advanced glycation end-products axis, and proliferation- and migration-related β-catenin, Yes-associated protein 1, Runt-related transcription factor 2, and TGF- β1/Smad signals. Therefore, exosomes and exosomal HMGB1 appear to have roles in platelet-driven cancer malignancy and represent targets of antiplatelet drugs in anticancer treatment.[3]

Apoptosis Analysis[2]
Cell Types: AML (OCI-AML-2, OCI-AML-3) cell line
Tested Concentrations: 5 μM
Incubation Duration: 48 h
Experimental Results: Induced apoptosis with the combination of fluvastatin and dipyridamole, cilostazol, forskolin, or dbcAMP in OCI-AML-2 and OCI-AML-3 cells.

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RT-PCR[2]
Cell Types: LP1 cell line
Tested Concentrations: 5 μM
Incubation Duration: 16 h
Experimental Results: Increased the sensibility of cancer cells to statin-induced apoptosis.

Animal/Disease Models: C57BL/6-LLC tumor-bearing mouse model [3]
Doses: 10 mg/kg
Route of Administration: po (oral gavage); 10 mg/kg; one time/day for 18 days
Experimental Results: Reduce tumors in tumor-bearing mice grow.

Absorption, Distribution and Excretion
70%
Dipyridamole is metabolized in the liver to the glucuronic acid conjugate and excreted with the bile.
1 to 2.5 L/kg
2.3-3.5 mL/min/kg

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Metabolism / Metabolites
hepatic

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Biological Half-Life
40 minutes

Hepatotoxicity
Dipyridamole has been associated with a low rate of serum enzyme elevations during therapy, but in large clinical trials the frequency of liver enzyme abnormalities was similar with dipyridamole therapy as with placebo. Cases of clinically apparent acute liver injury from dipyridamole have not been published although hepatitis is listed as a potential side effect in the product label. The clinical features of the liver injury linked to dipyridamole have not been described.
Likelihood score: E* (unproven but suspected cause of clinically apparent liver injury).
Drug Class: Antithrombotic Agents, Antiplatelet Agents
Other Drugs in the Subclass, Antiplatelet Agents: Aspirin, Cangrelor, Clopidogrel, Prasugrel, Ticagrelor, Ticlopidine, Vorapaxar

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No published information is available on the use of dipyridamole during breastfeeding, although labeling states that the drug is excreted into human milk. Until more data become available, dipyridamole should be used with caution during breastfeeding, especially while nursing a newborn or preterm infant. If it is used by a nursing mother, monitor the infant for bruising and bleeding.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
99%

[1]. Kerndt CC, Nagalli S. Dipyridamole. 2021 Nov 25. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan–. PMID: 32119342.

[2]. Longo, Joseph, etal. Cyclic AMP-hydrolyzing phosphodiesterase inhibitors potentiate statin-induced cancer cell death. Molecular oncology vol. 14,10 (2020): 2533-2545.

[3]. Wang, Jiaan-Der, etal. Exosomal HMGB1 Promoted Cancer Malignancy. Cancers vol. 13,4 877. 19 Feb. 2021.

Dipyridamole is a pyrimidopyrimidine that is 2,2',2'',2'''-(pyrimido[5,4-d]pyrimidine-2,6-diyldinitrilo)tetraethanol substituted by piperidin-1-yl groups at positions 4 and 8 respectively. A vasodilator agent, it inhibits the formation of blood clots. It has a role as an adenosine phosphodiesterase inhibitor, an EC 3.5.4.4 (adenosine deaminase) inhibitor, a platelet aggregation inhibitor and a vasodilator agent. It is a member of piperidines, a pyrimidopyrimidine, a tertiary amino compound and a tetrol.
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)
Dipyridamole is a Platelet Aggregation Inhibitor. The physiologic effect of dipyridamole is by means of Decreased Platelet Aggregation.
Dipyridamole is a vasodilator and inhibitor of platelet aggregation that is used to decrease the risk of thromboembolic complications and recurrence of stroke in patients known to have atherosclerotic cerebrovascular disease. Dipyridamole is associated with a low rate of serum enzyme elevations during treatment, but has not been linked to instances of clinically apparent acute liver injury.
Dipyridamole has been reported in Heracleum candicans and Prangos ferulacea with data available.
Dipyridamole is a synthetic agent derivative of pyrimido-pyrimidine, with antiplatelet properties. Dipyridamole inhibits adenosine uptake by platelets and endothelial cells, triggering an accumulation of cyclic adenosine monophosphate (cAMP), and inhibiting the stimulation of platelet aggregation by agents such as platelet activating factor and collagen. (NCI04)
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)
See also: Aspirin; Dipyridamole (component of).

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Drug 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.
FDA Label

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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.

C24H40N8O4

504.63

504.317

C, 57.12; H, 7.99; N, 22.21; O, 12.68

58-32-2

Dipyridamole-d20;1189983-52-5;Dipyridamole-d16

3108

Light yellow to yellow solid powder

1.4±0.1 g/cm3

806.5±75.0 °C at 760 mmHg

165-166ºC

441.5±37.1 °C

0.0±3.0 mmHg at 25°C

1.670

-1.22

4

12

12

36

561

0

IZEKFCXSFNUWAM-UHFFFAOYSA-N

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

2,2,2,2-((4,8-di(piperidin-1-yl)pyrimido[5,4-d]pyrimidine-2,6-diyl)bis(azanetriyl))tetraethanol

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: This product requires protection from light (avoid light exposure) during transportation and storage.

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

Solubility in Formulation 1: ≥ 2.5 mg/mL (4.95 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (4.95 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (4.95 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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