Identification

Name
Pentoxifylline
Accession Number
DB00806
Description

Pentoxifylline (PTX) is a synthetic dimethylxanthine derivative that modulates the rheological properties of blood and also has both anti-oxidant and anti-inflammatory properties.2,29 Although originally developed to treat intermittent claudication, a form of exertion-induced leg pain common in patients with peripheral arterial disease, PTX has been investigated for its possible use in diverse conditions, including osteoradionecrosis, diabetic kidney disease, and generally any condition associated with fibrosis.1,2,13 More recently, PTX has been suggested as a possible treatment for COVID-19-induced pulmonary complications due to its ability to regulate the production of inflammatory cytokines.28

Pentoxifylline has been marketed in Europe since 1972; PTX extended-release tablets sold under the trade name TRENTAL by US Pharm Holdings were first approved by the FDA on Aug 30, 1984, but have since been discontinued. A branded product, PENTOXIL, marketed by Upsher-Smith Laboratories, and generic forms marketed by Valeant Pharmaceuticals and APOTEX have been available since the late 1990s.29

Type
Small Molecule
Groups
Approved, Investigational
Structure
Thumb
Weight
Average: 278.307
Monoisotopic: 278.137890462
Chemical Formula
C13H18N4O3
Synonyms
  • Oxpentifylline
  • Pentoxifilina
  • Pentoxifyllin
  • Pentoxifylline
  • Pentoxifyllinum
External IDs
  • BL 191
  • BL-191
  • C04AD03
  • PTX

Pharmacology

Pharmacology
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Indication

Pentoxifylline is indicated for the treatment of intermittent claudication in patients with chronic occlusive arterial disease. Pentoxifylline may improve limb function and reduce symptoms but cannot replace other therapies such as surgical bypass or removal of vascular obstructions.29

Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

Pentoxifylline, a synthetic dimethylxanthine derivative structurally related to theophylline and caffeine, exhibits hemorheological, anti-oxidative, and anti-inflammatory properties and is traditionally indicated in the treatment of peripheral arterial disease (PAD). In PAD patients with concurrent cerebrovascular and coronary artery diseases, pentoxifylline treatment has occasionally been associated with angina, arrhythmia, and hypotension. Concurrent use with warfarin should be associated with more frequent monitoring of prothrombin times. Also, patients with risk factors complicated by hemorrhages, such as retinal bleeding, peptic ulceration, and recent surgery, should be monitored periodically for bleeding signs.29

Mechanism of action

Patients with peripheral arterial disease (PAD) may suffer from intermittent claudication, exertional leg pain that resolves upon rest, which is underscored by a complex etiology including vascular dysfunction (reduced limb perfusion, angiogenesis, and microcirculatory flow), systemic inflammation, and skeletal muscle dysfunction.1 Pentoxifylline (PTX), (3,7-dimethyl-1-(5-oxohexyl)-3,7-dihydro-1H-purine-2,6-dione) or 1-(5-oxohexyl)-3,7-­dimethylxanthine, is a methyl-xanthine derivative that acts to lower blood viscosity by increasing erythrocyte flexibility, reducing plasma fibrinogen, inhibiting neutrophil activation, and suppressing erythrocyte/platelet aggregation; it also has antioxidant and anti-inflammatory effects.2,29 Although the precise mechanism of action has yet to be elucidated, numerous studies have suggested several effects of PTX.

The classical interpretation of PTX's broad effects is due to its ability to act, in vitro, as a non-specific cyclic-3',5'-phosphodiesterase (PDE) inhibitor at millimolar concentrations; specifically, it has been proposed that inhibition of PDE type III and IV isozymes leads to elevated cyclic adenosine monophosphate (cAMP) levels, which mediate diverse downstream effects.3,4,5 This view has been challenged, specifically by observing those plasma concentrations of PTX in routine clinical use are typically only around 1μM, far lower than those used to inhibit PDEs in vitro.5 Instead, several studies have suggested that PTX can modulate adenosine receptor function, specifically the Gα-coupled A2A receptor (A2AR). Whether PTX acts directly as an A2AR agonist is unclear, although it can clearly increase the response of A2AR to adenosine.6,7,8,9 A2AR activation activates adenylyl cyclase, which increases intracellular cAMP levels; this observation may explain PTX's ability to increase intracellular cAMP in a PDE-independent fashion.10

Elevated cAMP levels have numerous downstream effects. cAMP-mediated activation of protein kinase A (PKA) suppresses nuclear translocation of NF-κB, which suppresses transcription of pro-inflammatory cytokines such as tumour necrosis factor (TNF-α), interleukin-1 (IL-1), and IL-6 as well as TNF-induced molecules such as adhesion molecules (ICAM1 and VCAM1) and the C-reactive protein (CRP).2,11,12,13 PTX has also been shown to prevent the downstream phosphorylation of p38 MAPK and ERK, which are responsible for assembling the NADPH oxidase involved in the neutrophil oxidative burst. This effect is due to a PKA-independent decrease in Akt phosphorylation and a PKA-dependent decrease in phosphorylation of p38 MAPK and ERK.12,15,16 This transcriptional regulation at least partially explains the anti-inflammatory and anti-oxidative properties of PTX.

Also, activated PKA can activate the cAMP response element-binding protein (CREB), which itself blocks SMAD-driven gene transcription, effectively disrupting transforming growth factor (TGF-β1) signalling.10,17 This results in lower levels of fibrinogenic molecules such as collagens, fibronectin, connective tissue growth factor, and alpha-smooth muscle actin.10,12,17,14 Hence, disruption of TGF-β1 signalling may explain the anti-fibrotic effects of PTX, including at least some of the decrease in blood viscosity.

The picture is complicated by the observation that PTX metabolites M1, M4, and M5 have been shown to inhibit C5 Des Arg- and formyl-methionylleucylphenylalanine-induced superoxide production in neutrophils and M1 and M5 significantly contribute to PTX's observed hemorheological effects.2,5,18 Overall, PTX administration is associated with decreased pro-inflammatory molecules, an increase in anti-inflammatory molecules such as IL-10, and decreased production of fibrinogenic and cellular adhesion molecules.

TargetActionsOrganism
AAdenosine receptor A2a
agonist
Humans
APhosphodiesterase enzymes
inhibitor
Humans
UAdenosine receptor A1Not AvailableHumans
U5'-nucleotidase
inhibitor
Humans
Absorption

Oral pentoxifylline (PTX) is almost completely absorbed but has low bioavailability of 20-30% due to extensive first-pass metabolism; three of the seven known metabolites, M1, M4, and M5 are present in plasma and appear soon after dosing.22,23,29 Single oral doses of 100, 200, and 400 mg of pentoxifylline in healthy males produced a mean tmax of 0.29-0.41 h, a mean Cmax of 272-1607 ng/mL, and a mean AUC0-∞ of 193-1229 ng*h/mL; corresponding ranges for metabolites 1, 4, and 5 were 0.72-1.15, 114-2753, and 189-7057.19 Single administration of a 400 mg extended-release tablet resulted in a heightened tmax of 2.08 ± 1.16 h, lowered Cmax of 55.33 ± 22.04 ng/mL, and a comparable AUC0-t of 516 ± 165 ng*h/mL; all these parameters were increased in cirrhotic patients.20

Smoking was associated with a decrease in the Cmax and AUCsteady-state of metabolite M1 but did not dramatically affect the pharmacokinetic parameters of pentoxifylline or other measured metabolites.21 Renal impairment increases the mean Cmax, AUC, and ratio to parent compound AUC of metabolites M4 and M5, but has no significant effect on PTX or M1 pharmacokinetics.22 Finally, similar to cirrhotic patients, the Cmax and tmax of PTX and its metabolites are increased in patients with varying degrees of chronic heart failure.23

Overall, metabolites M1 and M5 exhibit plasma concentrations roughly five and eight times greater than PTX, respectively. PTX and M1 pharmacokinetics are approximately dose-dependent, while those of M5 are not. Food intake before PTX ingestion delays time to peak plasma concentrations but not overall absorption. Extended-release forms of PTX extend the tmax to between two and four hours but also serves to ameliorate peaks and troughs in plasma concentration over time.29

Volume of distribution

Pentoxifylline has a volume of distribution of 4.15 ± 0.85 following a single intravenous 100 mg dose in healthy subjects.20

Protein binding

Pentoxifylline is approximately 45% bound to erythrocyte membranes.22

Metabolism

Pentoxifylline (PTX) metabolism is incompletely understood. There are seven known metabolites (M1 through M7), although only M1, M4, and M5 are detected in plasma at appreciable levels, following the general pattern M5 > M1 > PTX > M4.2,29 As PTX apparent clearance is higher than hepatic blood flow and the AUC ratio of M1 to PTX is not appreciably different in cirrhotic patients, it is clear that erythrocytes are the main site of PTX-M1 interconversion. However, the reaction likely occurs in the liver as well.20,24,25 PTX is reduced in an NADPH-dependent manner by unknown an unidentified carbonyl reductase to form either lisofylline (the (R)-M1 enantiomer) or (S)-M1; the reaction is stereoselective, producing (S)-M1 exclusively in liver cytosol, 85% (S)-M1 in liver microsomes, and a ratio of 0.010-0.025 R:S-M1 after IV or oral dosing in humans.24,25 Although both (R)- and (S)-M1 can be oxidized back into PTX, (R)-M1 can also give rise to M2 and M3 in liver microsomes.24,25 In vitro studies suggest that CYP1A2 is at least partly responsible for the conversion of lisofylline ((R)-M1) back into PTX.26 Unlike the reversible oxidation/reduction of PTX and its M1 metabolites, M4 and M5 are formed via irreversible oxidation of PTX in the liver.19,22,23,24,25 Studies in mice recapitulating the PTX-ciprofloxacin drug reaction suggest that CYP1A2 is responsible for the formation of M6 from PTX and of M7 from M1, both through de-methylation at position 7.27 In general, metabolites M2, M3, and M6 are formed at very low levels in mammals.19

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Route of elimination

Pentoxifylline is eliminated almost entirely in the urine and predominantly as M5, which accounts for between 57 and 65 percent of the administered dose. Smaller amounts of M4 are recovered, while M1 and the parent compound account for less than 1% of the recovered dose. The fecal route accounts for less than 4% of the administered dose.2,19,29

Half-life

Overall, pentoxifylline has an elimination half-life of between 0.39 and 0.84 hours, while its primary metabolites have elimination half-lives of between 0.96 and 1.61 hours.2

Clearance

Pentoxifylline given as a single 100 mg intravenous infusion has a clearance of 3.62 ± 0.75 L/h/kg in healthy subjects, which decreased to 1.44 ± 0.46 L/h/kg in cirrhotic patients.20 In another study, the apparent clearance of either 300 or 600 mg of pentoxifylline given intravenously (median and range) was 4.2 (2.8-6.3) and 4.1 (2.3-4.6) L/min, respectively.25 It is important to note that, due to the reversible extra-hepatic metabolism of the parent compound and metabolite 1, the true clearance of pentoxifylline may be even higher than the measured values.25

Adverse Effects
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Toxicity

Overdoses of pentoxifylline have been reported with symptoms including agitation, fever, flushing, hypotension, convulsions, somnolence, and loss of consciousness beginning 4-5 hours following ingestion and lasting up to 12 hours. Symptomatic treatment is recommended, specifically pertaining to maintaining proper respiration, blood pressure, and controlling convulsions. Activated charcoal may prove useful in absorbing excess pentoxifylline in overdose cases. Patients have recovered from overdose even at doses as high as 80 mg/kg.29

Affected organisms
  • Humans and other mammals
Pathways
Not Available
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
AbacavirPentoxifylline may decrease the excretion rate of Abacavir which could result in a higher serum level.
AbametapirThe serum concentration of Pentoxifylline can be increased when it is combined with Abametapir.
AbataceptThe metabolism of Pentoxifylline can be increased when combined with Abatacept.
AbciximabThe therapeutic efficacy of Abciximab can be increased when used in combination with Pentoxifylline.
AbirateroneThe serum concentration of Pentoxifylline can be increased when it is combined with Abiraterone.
AcebutololPentoxifylline may increase the hypotensive activities of Acebutolol.
AceclofenacThe risk or severity of bleeding can be increased when Aceclofenac is combined with Pentoxifylline.
AcemetacinThe risk or severity of bleeding can be increased when Acemetacin is combined with Pentoxifylline.
AcenocoumarolThe therapeutic efficacy of Acenocoumarol can be increased when used in combination with Pentoxifylline.
AcetaminophenThe metabolism of Pentoxifylline can be decreased when combined with Acetaminophen.
Interactions
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Food Interactions
  • Limit caffeine intake.
  • Take with food. Administration with food may reduce irritation. Co-administration with food modestly increases the mean pentoxifylline AUC and maximum plasma concentrations (1.1- and 1.3-fold, respectively) achieved with an extended-release tablet.

Products

Products
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Product Images
International/Other Brands
Agapurin (Zentiva) / Agapurin SR (Zentiva) / An Ruo Ning (Nanjing Yaoda Bio-Pharmaceutical) / Angiopent (Helcor) / Ao Le Ni (C & O Pharmaceuticals) / Ao Nuo Hong (AosaiKang Pharmaceutical) / Aotong (Treeful Pharmaceutical) / Azupentat / Behrifil (Sanofi-Aventis) / Bo Shu Te (Jisheng Pharmaceutical) / Claudicat (Nycomed) / Durapental (Mylan dura) / Elorgan (Sanofi Aventis) / Endopentoksas (Endokriniai) / Pentilin (Krka) / Pentilin Retard (Krka) / Pentoflux (Bouchara-Recordati) / Pentofyllin (Sopharma) / Pentoksifilin (Panfarma) / Pentolab (Lamsa) / Pentomer (ratiopharm) / Rentylin (Amdipharm) / Torental (Sanofi-Aventis) / Trentilin Retard (Santa-Farma)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Pentoxifylline SRTablet, extended releaseOralAa Pharma Inc1997-01-14Not applicableCanada flag
TrentalTablet, film coated400 mg/1OralPhysicians Total Care, Inc.1984-08-302011-09-30US flag
TrentalTablet, film coated, extended release400 mg/1OralSanofi Aventis1984-08-302013-12-31US flag
TrentalTablet, extended release400 mgOralSanofi Aventis1996-10-232013-03-01Canada flag
Trental Srt 400mgTablet, extended releaseOralHoechst Roussel Canada Inc.1993-12-311998-08-12Canada flag
Trental Tab 400mgTablet, extended releaseOralHoechst Canada Inc.1984-12-311996-08-29Canada flag
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Nu-pentoxifylline-SR 400 mgTablet, extended releaseOralNu Pharm Inc1998-03-182012-09-04Canada flag
PentoxifyllineTablet, extended release400 mg/1OralAv Kare, Inc.2013-07-312017-11-01US flag
PentoxifyllineTablet, film coated, extended release400 mg/1OralMylan Institutional Inc.1998-01-152019-05-31US flag
PentoxifyllineTablet, extended release400 mg/1OralStat Rx USA1998-07-20Not applicableUS flag16590 085620210331 17394 1kkes28
PentoxifyllineTablet, extended release400 mg/1OralNucare Pharmaceuticals, Inc.1999-06-10Not applicableUS flag
PentoxifyllineTablet, extended release400 mg/1OralAphena Pharma Solutions Tennessee, Inc.1999-06-10Not applicableUS flag
PentoxifyllineTablet, extended release400 mg/1OralMajor Pharmaceuticals1999-06-10Not applicableUS flag
PentoxifyllineTablet, film coated, extended release400 mg/1OralState of Florida DOH Central Pharmacy2009-07-01Not applicableUS flag53808 051620180907 15195 1r0m9hs
PentoxifyllineTablet, extended release400 mg/1Oralbryant ranch prepack1999-06-10Not applicableUS flag63629 291020180907 15195 19l564t
PentoxifyllineTablet, extended release400 mg/1OralNucare Pharmaceuticals,inc.2014-08-22Not applicableUS flag
Unapproved/Other Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
Betamethasone Dipropionate 0.05% / Minoxidil 5% / Niacinamide 2% / Pentoxifylline 0.5%Pentoxifylline (2 g/100g) + Betamethasone dipropionate (0.05 g/100g) + Minoxidil (5 g/100g) + Nicotinamide (2 g/100g)SolutionTopicalSincerus Florida, LLC2019-05-09Not applicableUS flag
Gapeam BudibacPentoxifylline (1 g/1g) + Amantadine hydrochloride (1 g/1g) + Baclofen (1 g/1g) + Bupivacaine hydrochloride anhydrous (1 g/1g) + Cyclobenzaprine hydrochloride (1 g/1g) + Diclofenac sodium (1 g/1g) + Gabapentin (1 g/1g)KitTopicalAlvix Laboratories2014-12-052018-03-08US flag
Pentoxifylline 0.5% / Triamcinolone Acetonide 0.1%Pentoxifylline (0.5 g/100g) + Triamcinolone acetonide (0.1 g/100g)GelTopicalSincerus Florida, LLC2019-05-15Not applicableUS flag

Categories

ATC Codes
C04AD03 — PentoxifyllineR03DA20 — Combinations of xanthines
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as xanthines. These are purine derivatives with a ketone group conjugated at carbons 2 and 6 of the purine moiety.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Imidazopyrimidines
Sub Class
Purines and purine derivatives
Direct Parent
Xanthines
Alternative Parents
6-oxopurines / Alkaloids and derivatives / Pyrimidones / N-substituted imidazoles / Vinylogous amides / Heteroaromatic compounds / Ureas / Lactams / Ketones / Azacyclic compounds
show 4 more
Substituents
6-oxopurine / Alkaloid or derivatives / Aromatic heteropolycyclic compound / Azacycle / Azole / Carbonyl group / Heteroaromatic compound / Hydrocarbon derivative / Imidazole / Ketone
show 14 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
oxopurine (CHEBI:7986)

Chemical Identifiers

UNII
SD6QCT3TSU
CAS number
6493-05-6
InChI Key
BYPFEZZEUUWMEJ-UHFFFAOYSA-N
InChI
InChI=1S/C13H18N4O3/c1-9(18)6-4-5-7-17-12(19)10-11(14-8-15(10)2)16(3)13(17)20/h8H,4-7H2,1-3H3
IUPAC Name
3,7-dimethyl-1-(5-oxohexyl)-2,3,6,7-tetrahydro-1H-purine-2,6-dione
SMILES
CN1C=NC2=C1C(=O)N(CCCCC(C)=O)C(=O)N2C

References

General References
  1. Hamburg NM, Creager MA: Pathophysiology of Intermittent Claudication in Peripheral Artery Disease. Circ J. 2017 Feb 24;81(3):281-289. doi: 10.1253/circj.CJ-16-1286. Epub 2017 Jan 26. [PubMed:28123169]
  2. Wen WX, Lee SY, Siang R, Koh RY: Repurposing Pentoxifylline for the Treatment of Fibrosis: An Overview. Adv Ther. 2017 Jun;34(6):1245-1269. doi: 10.1007/s12325-017-0547-2. Epub 2017 May 8. [PubMed:28484954]
  3. Meskini N, Nemoz G, Okyayuz-Baklouti I, Lagarde M, Prigent AF: Phosphodiesterase inhibitory profile of some related xanthine derivatives pharmacologically active on the peripheral microcirculation. Biochem Pharmacol. 1994 Mar 2;47(5):781-8. doi: 10.1016/0006-2952(94)90477-4. [PubMed:8135854]
  4. Windmeier C, Gressner AM: Pharmacological aspects of pentoxifylline with emphasis on its inhibitory actions on hepatic fibrogenesis. Gen Pharmacol. 1997 Aug;29(2):181-96. doi: 10.1016/s0306-3623(96)00314-x. [PubMed:9251897]
  5. McCarty MF, O'Keefe JH, DiNicolantonio JJ: Pentoxifylline for vascular health: a brief review of the literature. Open Heart. 2016 Feb 8;3(1):e000365. doi: 10.1136/openhrt-2015-000365. eCollection 2016. [PubMed:26870389]
  6. Schwabe U, Ukena D, Lohse MJ: Xanthine derivatives as antagonists at A1 and A2 adenosine receptors. Naunyn Schmiedebergs Arch Pharmacol. 1985 Sep;330(3):212-21. [PubMed:2997628]
  7. Kreth S, Ledderose C, Luchting B, Weis F, Thiel M: Immunomodulatory properties of pentoxifylline are mediated via adenosine-dependent pathways. Shock. 2010 Jul;34(1):10-6. doi: 10.1097/SHK.0b013e3181cdc3e2. [PubMed:19997047]
  8. Konrad FM, Neudeck G, Vollmer I, Ngamsri KC, Thiel M, Reutershan J: Protective effects of pentoxifylline in pulmonary inflammation are adenosine receptor A2A dependent. FASEB J. 2013 Sep;27(9):3524-35. doi: 10.1096/fj.13-228122. Epub 2013 May 22. [PubMed:23699177]
  9. Li H, Tan G, Tong L, Han P, Zhang F, Liu B, Sun X: Pentoxifylline inhibits pulmonary inflammation induced by infrarenal aorticcross-clamping dependent of adenosine receptor A2A. Am J Transl Res. 2016 May 15;8(5):2210-21. eCollection 2016. [PubMed:27347328]
  10. Schulte G, Fredholm BB: Signalling from adenosine receptors to mitogen-activated protein kinases. Cell Signal. 2003 Sep;15(9):813-27. doi: 10.1016/s0898-6568(03)00058-5. [PubMed:12834807]
  11. Chen YM, Chiang WC, Yang Y, Lai CF, Wu KD, Lin SL: Pentoxifylline Attenuates Proteinuria in Anti-Thy1 Glomerulonephritis via Downregulation of Nuclear Factor-kappaB and Smad2/3 Signaling. Mol Med. 2015 Apr 13;21:276-84. doi: 10.2119/molmed.2015.00023. [PubMed:25879629]
  12. Chen YM, Chiang WC, Lin SL, Tsai TJ: Therapeutic efficacy of pentoxifylline on proteinuria and renal progression: an update. J Biomed Sci. 2017 Nov 13;24(1):84. doi: 10.1186/s12929-017-0390-4. [PubMed:29132351]
  13. Donate-Correa J, Tagua VG, Ferri C, Martin-Nunez E, Hernandez-Carballo C, Urena-Torres P, Ruiz-Ortega M, Ortiz A, Mora-Fernandez C, Navarro-Gonzalez JF: Pentoxifylline for Renal Protection in Diabetic Kidney Disease. A Model of Old Drugs for New Horizons. J Clin Med. 2019 Feb 27;8(3). pii: jcm8030287. doi: 10.3390/jcm8030287. [PubMed:30818852]
  14. Chen YM, Wu KD, Tsai TJ, Hsieh BS: Pentoxifylline inhibits PDGF-induced proliferation of and TGF-beta-stimulated collagen synthesis by vascular smooth muscle cells. J Mol Cell Cardiol. 1999 Apr;31(4):773-83. doi: 10.1006/jmcc.1998.0910. [PubMed:10329205]
  15. Costantini TW, Deree J, Peterson CY, Putnam JG, Woon T, Loomis WH, Bansal V, Coimbra R: Pentoxifylline modulates p47phox activation and downregulates neutrophil oxidative burst through PKA-dependent and -independent mechanisms. Immunopharmacol Immunotoxicol. 2010 Mar;32(1):82-91. doi: 10.3109/08923970903183557. [PubMed:19839729]
  16. Deree J, Melbostad H, Loomis WH, Putnam JG, Coimbra R: The effects of a novel resuscitation strategy combining pentoxifylline and hypertonic saline on neutrophil MAPK signaling. Surgery. 2007 Aug;142(2):276-83. doi: 10.1016/j.surg.2007.04.008. [PubMed:17689696]
  17. Lyons AJ, Brennan PA: Pentoxifylline - a review of its use in osteoradionecrosis. Br J Oral Maxillofac Surg. 2017 Apr;55(3):230-234. doi: 10.1016/j.bjoms.2016.12.006. Epub 2016 Dec 27. [PubMed:28034471]
  18. Crouch SP, Fletcher J: Effect of ingested pentoxifylline on neutrophil superoxide anion production. Infect Immun. 1992 Nov;60(11):4504-9. doi: 10.1128/IAI.60.11.4504-4509.1992. [PubMed:1356929]
  19. Smith RV, Waller ES, Doluisio JT, Bauza MT, Puri SK, Ho I, Lassman HB: Pharmacokinetics of orally administered pentoxifylline in humans. J Pharm Sci. 1986 Jan;75(1):47-52. doi: 10.1002/jps.2600750111. [PubMed:3958905]
  20. Rames A, Poirier JM, LeCoz F, Midavaine M, Lecocq B, Grange JD, Poupon R, Cheymol G, Jaillon P: Pharmacokinetics of intravenous and oral pentoxifylline in healthy volunteers and in cirrhotic patients. Clin Pharmacol Ther. 1990 Mar;47(3):354-9. doi: 10.1038/clpt.1990.39. [PubMed:2178853]
  21. Mauro VF, Mauro LS, Hageman JH: Comparison of pentoxifylline pharmacokinetics between smokers and nonsmokers. J Clin Pharmacol. 1992 Nov;32(11):1054-8. doi: 10.1002/j.1552-4604.1992.tb03811.x. [PubMed:1474168]
  22. Paap CM, Simpson KS, Horton MW, Schaefer KL, Lassman HB, Sack MR: Multiple-dose pharmacokinetics of pentoxifylline and its metabolites during renal insufficiency. Ann Pharmacother. 1996 Jul-Aug;30(7-8):724-9. doi: 10.1177/106002809603000702. [PubMed:8826548]
  23. Nisi A, Panfili M, De Rosa G, Boffa G, Groppa F, Gusella M, Padrini R: Pharmacokinetics of pentoxifylline and its main metabolites in patients with different degrees of heart failure following a single dose of a modified-release formulation. J Clin Pharmacol. 2013 Jan;53(1):51-7. doi: 10.1177/0091270011433435. Epub 2013 Jan 24. [PubMed:23400743]
  24. Lillibridge JA, Kalhorn TF, Slattery JT: Metabolism of lisofylline and pentoxifylline in human liver microsomes and cytosol. Drug Metab Dispos. 1996 Nov;24(11):1174-9. [PubMed:8937849]
  25. Nicklasson M, Bjorkman S, Roth B, Jonsson M, Hoglund P: Stereoselective metabolism of pentoxifylline in vitro and in vivo in humans. Chirality. 2002 Aug;14(8):643-52. doi: 10.1002/chir.10121. [PubMed:12125034]
  26. Lee SH, Slattery JT: Cytochrome P450 isozymes involved in lisofylline metabolism to pentoxifylline in human liver microsomes. Drug Metab Dispos. 1997 Dec;25(12):1354-8. [PubMed:9394024]
  27. Peterson TC, Peterson MR, Wornell PA, Blanchard MG, Gonzalez FJ: Role of CYP1A2 and CYP2E1 in the pentoxifylline ciprofloxacin drug interaction. Biochem Pharmacol. 2004 Jul 15;68(2):395-402. doi: 10.1016/j.bcp.2004.03.035. [PubMed:15194011]
  28. Hendry BM, Stafford N, Arnold AD, Sangwaiya A, Manglam V, Rosen SD, Arnold J: Hypothesis: Pentoxifylline is a potential cytokine modulator therapeutic in COVID-19 patients. Pharmacol Res Perspect. 2020 Aug;8(4):e00631. doi: 10.1002/prp2.631. [PubMed:32715661]
  29. FDA Approved Drug Products: TRENTAL (pentoxifylline) tablets [Link]
  30. MSDS: pentoxifylline [Link]
Human Metabolome Database
HMDB0014944
KEGG Drug
D00501
KEGG Compound
C07424
PubChem Compound
4740
PubChem Substance
46505940
ChemSpider
4578
BindingDB
10850
RxNav
8013
ChEBI
7986
ChEMBL
CHEMBL628
ZINC
ZINC000001530776
Therapeutic Targets Database
DAP000048
PharmGKB
PA450864
PDBe Ligand
PNX
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Pentoxifylline
AHFS Codes
  • 20:24.00 — Hemorrheologic Agents
PDB Entries
2a3c / 3arr / 3aru / 3tvx
FDA label
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MSDS
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Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4Active Not RecruitingTreatmentLumbar Disc Disease / Lumbar Radiculopathy / Prolapsed Lumbar Disc1
4CompletedPreventionDiabetic Nephropathy1
4CompletedTreatmentBMI >30 kg/m21
4CompletedTreatmentChronic Kidney Disease (CKD)1
4CompletedTreatmentEnd Stage Renal Disease (ESRD) / Hemodialysis Treatment / Inflammatory Reaction1
4CompletedTreatmentOsteoradionecrosis1
4CompletedTreatmentSevere Alcoholic Hepatitis1
4CompletedTreatmentType 2 Diabetes Mellitus1
4Not Yet RecruitingTreatmentDecompensated Heart Failure / Hemolysis Intravascular1
4RecruitingTreatmentChronic Kidney Disease stage3 and 4 / Type 2 Diabetes Mellitus1

Pharmacoeconomics

Manufacturers
  • Actavis elizabeth llc
  • Apotex inc
  • Biovail laboratories inc
  • Heritage pharmaceuticals inc
  • Impax laboratories inc
  • Mylan pharmaceuticals inc
  • Pliva inc
  • Teva pharmaceuticals usa inc
  • Watson laboratories inc
  • Upsher smith laboratories inc
  • Sanofi aventis us llc
Packagers
  • Amerisource Health Services Corp.
  • Amneal Pharmaceuticals
  • Apotex Inc.
  • A-S Medication Solutions LLC
  • Atlantic Biologicals Corporation
  • Biovail Pharmaceuticals
  • Cardinal Health
  • Dept Health Central Pharmacy
  • Dispensing Solutions
  • Diversified Healthcare Services Inc.
  • Gallipot
  • Golden State Medical Supply Inc.
  • Heartland Repack Services LLC
  • Lake Erie Medical and Surgical Supply
  • Major Pharmaceuticals
  • Mckesson Corp.
  • Merrell Pharmaceuticals Inc.
  • Murfreesboro Pharmaceutical Nursing Supply
  • Mylan
  • Nucare Pharmaceuticals Inc.
  • Pharmedix
  • Physicians Total Care Inc.
  • Pliva Inc.
  • Prepak Systems Inc.
  • Remedy Repack
  • Sandhills Packaging Inc.
  • Sanofi-Aventis Inc.
  • Southwood Pharmaceuticals
  • Teva Pharmaceutical Industries Ltd.
  • Torpharm Inc.
  • Tya Pharmaceuticals
  • UDL Laboratories
  • Upsher Smith Laboratories
  • Va Cmop Dallas
  • Vangard Labs Inc.
  • Zoetica Pharmaceutical Corp.
Dosage Forms
FormRouteStrength
SolutionTopical
KitTopical
InjectionIntravenous
Capsule, coated pelletsOral
TabletOral
Tablet, film coatedOral
Tablet, extended releaseOral400 mg
Capsule
Tablet, extended releaseOral
PowderNot applicable1 g/1g
Tablet, extended releaseOral400 mg/1
Tablet, film coated, extended releaseOral400 mg/1
GelTopical
Injection
Tablet, sugar coatedOral
Injection, solutionIntravenous
Tablet, film coatedOral400 mg/1
Tablet, film coatedOral400 mg
ConcentrateIntravenous
SolutionIntravenous
Injection, solution, concentrateIntravenous
InjectionIntramuscular; Intravenous
Tablet, coatedOral
Prices
Unit descriptionCostUnit
TRENtal 400 mg Controlled Release Tabs1.4USD tab
Trental er 400 mg tablet1.27USD tablet
Pentoxifylline powder0.91USD g
Trental 400 mg Sustained-Release Tablet0.88USD tablet
Pentoxifylline 400 mg tablet sa0.71USD tablet
Pentoxifylline CR 400 mg Controlled Release Tabs0.62USD tab
Pentoxil 400 mg Controlled Release Tabs0.62USD tab
Pentoxil er 400 mg tablet0.62USD tablet
Pentoxifylline er 400 mg tablet0.6USD tablet
Apo-Pentoxifylline Sr 400 mg Sustained-Release Tablet0.4USD tablet
Nu-Pentoxifylline-Sr 400 mg Sustained-Release Tablet0.4USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)105 °CNot Available
water solubility7.7E+004 mg/L (at 25 °C)MERCK INDEX (1996)
logP0.29BIOBYTE (1995)
Predicted Properties
PropertyValueSource
logP0.23ChemAxon
pKa (Strongest Acidic)19.64ChemAxon
pKa (Strongest Basic)-1.2ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area75.51 Å2ChemAxon
Rotatable Bond Count5ChemAxon
Refractivity73.52 m3·mol-1ChemAxon
Polarizability29.27 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+1.0
Blood Brain Barrier+0.9851
Caco-2 permeable-0.5056
P-glycoprotein substrateSubstrate0.595
P-glycoprotein inhibitor INon-inhibitor0.6905
P-glycoprotein inhibitor IIInhibitor0.7157
Renal organic cation transporterNon-inhibitor0.7023
CYP450 2C9 substrateNon-substrate0.7897
CYP450 2D6 substrateNon-substrate0.9117
CYP450 3A4 substrateSubstrate0.6511
CYP450 1A2 substrateInhibitor0.9107
CYP450 2C9 inhibitorNon-inhibitor0.9518
CYP450 2D6 inhibitorNon-inhibitor0.943
CYP450 2C19 inhibitorNon-inhibitor0.9313
CYP450 3A4 inhibitorNon-inhibitor0.9827
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.901
Ames testNon AMES toxic0.7131
CarcinogenicityNon-carcinogens0.8965
BiodegradationNot ready biodegradable0.7457
Rat acute toxicity2.4070 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.6463
hERG inhibition (predictor II)Non-inhibitor0.8734
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-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSNot Available
MS/MS Spectrum - , positiveLC-MS/MSsplash10-0059-1890000000-c9be2fe26b2862cba4f5
MS/MS Spectrum - , positiveLC-MS/MSsplash10-001r-2900000000-d54457aaede5317cef72
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-0059-2970000000-95d1edcd63b61b13b22e

Targets

Drugtargets
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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Agonist
General Function
Identical protein binding
Specific Function
Receptor for adenosine. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase.
Gene Name
ADORA2A
Uniprot ID
P29274
Uniprot Name
Adenosine receptor A2a
Molecular Weight
44706.925 Da
References
  1. Kreth S, Ledderose C, Luchting B, Weis F, Thiel M: Immunomodulatory properties of pentoxifylline are mediated via adenosine-dependent pathways. Shock. 2010 Jul;34(1):10-6. doi: 10.1097/SHK.0b013e3181cdc3e2. [PubMed:19997047]
  2. Konrad FM, Neudeck G, Vollmer I, Ngamsri KC, Thiel M, Reutershan J: Protective effects of pentoxifylline in pulmonary inflammation are adenosine receptor A2A dependent. FASEB J. 2013 Sep;27(9):3524-35. doi: 10.1096/fj.13-228122. Epub 2013 May 22. [PubMed:23699177]
2. Phosphodiesterase enzymes
Kind
Group
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
Curator comments
It is unclear if pentoxifylline inhibition of phosphodiesterases in vivo at clinically achieved concentrations is relevant or not.
A group consisting of various phosphodiesterase enzymes
References
  1. Gresele P, Momi S, Falcinelli E: Anti-platelet therapy: phosphodiesterase inhibitors. Br J Clin Pharmacol. 2011 Oct;72(4):634-46. doi: 10.1111/j.1365-2125.2011.04034.x. [PubMed:21649691]
  2. Kruuse C, Jacobsen TB, Thomsen LL, Hasselbalch SG, Frandsen EK, Dige-Petersen H, Olesen J: Effects of the non-selective phosphodiesterase inhibitor pentoxifylline on regional cerebral blood flow and large arteries in healthy subjects. Eur J Neurol. 2000 Nov;7(6):629-38. doi: 10.1046/j.1468-1331.2000.00116.x. [PubMed:11136348]
  3. Swierczek A, Wyska E, Bas S, Woyciechowska M, Mlynarski J: PK/PD studies on non-selective PDE inhibitors in rats using cAMP as a marker of pharmacological response. Naunyn Schmiedebergs Arch Pharmacol. 2017 Oct;390(10):1047-1059. doi: 10.1007/s00210-017-1406-z. Epub 2017 Jul 20. [PubMed:28730281]
  4. Meskini N, Nemoz G, Okyayuz-Baklouti I, Lagarde M, Prigent AF: Phosphodiesterase inhibitory profile of some related xanthine derivatives pharmacologically active on the peripheral microcirculation. Biochem Pharmacol. 1994 Mar 2;47(5):781-8. doi: 10.1016/0006-2952(94)90477-4. [PubMed:8135854]
  5. Windmeier C, Gressner AM: Pharmacological aspects of pentoxifylline with emphasis on its inhibitory actions on hepatic fibrogenesis. Gen Pharmacol. 1997 Aug;29(2):181-96. doi: 10.1016/s0306-3623(96)00314-x. [PubMed:9251897]
  6. McCarty MF, O'Keefe JH, DiNicolantonio JJ: Pentoxifylline for vascular health: a brief review of the literature. Open Heart. 2016 Feb 8;3(1):e000365. doi: 10.1136/openhrt-2015-000365. eCollection 2016. [PubMed:26870389]
Details
3. Adenosine receptor A1
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Purine nucleoside binding
Specific Function
Receptor for adenosine. The activity of this receptor is mediated by G proteins which inhibit adenylyl cyclase.
Gene Name
ADORA1
Uniprot ID
P30542
Uniprot Name
Adenosine receptor A1
Molecular Weight
36511.325 Da
References
  1. Daly JW, Jacobson KA, Ukena D: Adenosine receptors: development of selective agonists and antagonists. Prog Clin Biol Res. 1987;230:41-63. [PubMed:3588607]
  2. Schwabe U, Ukena D, Lohse MJ: Xanthine derivatives as antagonists at A1 and A2 adenosine receptors. Naunyn Schmiedebergs Arch Pharmacol. 1985 Sep;330(3):212-21. [PubMed:2997628]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Nucleotide binding
Specific Function
Hydrolyzes extracellular nucleotides into membrane permeable nucleosides. Exhibits AMP-, NAD-, and NMN-nucleosidase activities.
Gene Name
NT5E
Uniprot ID
P21589
Uniprot Name
5'-nucleotidase
Molecular Weight
63367.255 Da
References
  1. Ustunsoy H, Sivrikoz MC, Tarakcioglu M, Bakir K, Guldur E, Celkan MA: The effects of pentoxifylline on the myocardial inflammation and ischemia-reperfusion injury during cardiopulmonary bypass. J Card Surg. 2006 Jan-Feb;21(1):57-61. [PubMed:16426349]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Curator comments
CYP1A2 appears important both for the oxidation of metabolite M1 back to parent compound and for the formation of metabolites M6 and M7 from pentoxifylline and M1, respectively.
General Function
Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP1A2
Uniprot ID
P05177
Uniprot Name
Cytochrome P450 1A2
Molecular Weight
58293.76 Da
References
  1. Lee SH, Slattery JT: Cytochrome P450 isozymes involved in lisofylline metabolism to pentoxifylline in human liver microsomes. Drug Metab Dispos. 1997 Dec;25(12):1354-8. [PubMed:9394024]
  2. Zhou SF, Yang LP, Zhou ZW, Liu YH, Chan E: Insights into the substrate specificity, inhibitors, regulation, and polymorphisms and the clinical impact of human cytochrome P450 1A2. AAPS J. 2009 Sep;11(3):481-94. doi: 10.1208/s12248-009-9127-y. Epub 2009 Jul 10. [PubMed:19590965]
  3. Peterson TC, Peterson MR, Wornell PA, Blanchard MG, Gonzalez FJ: Role of CYP1A2 and CYP2E1 in the pentoxifylline ciprofloxacin drug interaction. Biochem Pharmacol. 2004 Jul 15;68(2):395-402. doi: 10.1016/j.bcp.2004.03.035. [PubMed:15194011]

Drug created on June 13, 2005 13:24 / Updated on April 20, 2021 12:57