Identification
- Summary
Doxofylline is a methylxanthine derivative used in chronic obstructive pulmonary disease, asthma, and bronchospasms.
- Generic Name
- Doxofylline
- DrugBank Accession Number
- DB09273
- Background
Doxofylline is a methylxanthine derivative with the presence of a dioxolane group in position 7. As a drug used in the treatment of asthma, doxofylline has shown similar efficacy to theophylline but with significantly fewer side effects in animal and human studies. In contrast with other xanthine derivatives, doxofylline does not significantly bind to adenosine alpha-1 or alpha-2 receptors and lacks stimulating effects. Decreased affinity for adenosine receptors may account for the better safety profile of doxofylline compared to theophylline 9. Unlike theophylline, doxofylline does not affect calcium influx and does not antagonize the actions of calcium channel blockers which could explain reduced cardiac adverse reactions associated with the drug 5. The anti-asthmatic effects of doxophylline are mediated by other mechanisms, primarily through inhibiting the activities of the phosphodiesterase (PDE) enzyme.
- Type
- Small Molecule
- Groups
- Experimental
- Structure
Structure for Doxofylline (DB09273)
- Weight
- Average: 266.257
Monoisotopic: 266.101504947 - Chemical Formula
- C11H14N4O4
- Synonyms
- doxofilina
- Doxofylline
- Doxophylline
- External IDs
- ABC 12/3
Pharmacology
- Indication
Indicated for the treatment of chronic obstructive pulmonary disease (COPD), bronchial asthma and pulmonary disease with spastic bronchial component.
Reduce drug development failure ratesBuild, train, & validate machine-learning modelswith evidence-based and structured datasets.Build, train, & validate predictive machine-learning models with structured datasets.- Associated Conditions
Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Used in combination to treat Bronchial asthma Combination Product in combination with: Acetylcysteine (DB06151) •••••••••••• ••••••• •••••••••••• Treatment of Bronchial asthma •••••••••••• ••••••• •••••••••••• Treatment of Bronchial asthma •••••••••••• •••••••• ••• ••••••••• •••••••••• ••••••••• ••••••• ••• ••••••••• •••••• •••••• Used in combination to treat Chronic obstructive pulmonary disease (copd) Combination Product in combination with: Acetylcysteine (DB06151) •••••••••••• ••••••• •••••••••••• Treatment of Chronic obstructive pulmonary disease (copd) •••••••••••• ••••••• •••••••••••• - Contraindications & Blackbox Warnings
Prevent Adverse Drug Events TodayTap into our Clinical API for life-saving information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.Avoid life-threatening adverse drug events with our Clinical API- Pharmacodynamics
Doxofylline is a methylxanthine bronchodilator with potent bronchodilator activity comparable to that of theophylline. In animal studies, doxofylline demonstrated to attenuate bronchoconstriction, inflammatory actions and the release of thromboxane A2 (TXA2) when challenged with platelet-activating factor 9.
Doxofylline does not demonstrate direct inhibition of any histone deacetylase (HDAC) enzymes or known PDE enzyme isoforms and did not act as an antagonist at A2 or A2 receptors. The affinity for adenosine A1, A2A and A2B receptors are reported to be all higher than 100 µM 6. It only displays an inhibitory action against PDE2A1 and antagonism at adenosine A(2A) at high concentrations 7. A study demonstrated that doxofylline interacts with β2-adrenoceptors to induce blood vessel relaxation and airway smooth muscle relaxation. In dog studies, doxofylline decreased airway responsiveness at a dose that did not affect heart rate and respiratory rate 6.
- Mechanism of action
The main mechanism of action of doxofylline is unclear. One of the mechanisms of action of is thought to arise from the inhibition of phosphodiesterase activity thus increasing the levels of cAMP and promoting smooth muscle relaxation.
The interaction of doxofylline with beta-2 adrenoceptors was demonstrated by a study using nonlinear chromatography, frontal analysis and molecular docking 8. Serine 169 and serine 173 residues in the receptor are thought to be critical binding sites for doxofylline where hydrogen bonds are formed 8. Via mediating the actions of beta-2 adrenoceptors, doxofylline induces blood vessel relaxation and airway smooth muscle relaxation.
There is also evidence that doxofylline may exert anti-inflammatory actions by reducing the pleurisy induced by the inflammatory mediator platelet activating factor (PAF) according to a rat study 8. It is suggested that doxofylline may play an important role in attenuating leukocyte diapedesis, supported by mouse preclinical studies where doxofylline administration was associated with inhibited leukocyte migration across vascular endothelial cells in vivo and in vitro 6.Unlike theophylline, doxofylline does not inhibit tumor necrosis factor-induced interleukin (IL)-8 secretion in ASM cells.
Target Actions Organism ABeta-2 adrenergic receptor agonistHumans UAdenosine receptor A2a antagonistHumans AcGMP-dependent 3',5'-cyclic phosphodiesterase inhibitorHumans - Absorption
After repeated administrations doxofylline reaches the steady-state in about 4 days. Following oral administration of 400 mg doxofylline twice daily for 5 days in adults with chronic bronchitis, the peak plasma concentrations (Cmax) at steady state ranged from 5.78 to 20.76 mcg/mL. The time to reach maximum concentration (Tmax) was 1.19 ± 0.19 hours 9. The absolute bioavailability of doxofylline in healthy subjects was 63 ± 25% 9.
- Volume of distribution
Doxofylline demonstrates a short distribution phase following intravenous administration of 100 mg given in adults with chronic bronchitis 9. As methylxanthines are distributed to all body compartments, doxofylline may be detected in breast milk and placenta 9.
- Protein binding
At pH 7.4, the fraction of plasma protein binding is about 48% 11.
- Metabolism
Doxofylline is thought to undergo hepatic metabolism which accounts for 90% of total drug clearance 11. β-hydroxymethyltheophylline was detected in the serum and urine after oral administration of 400 mg given in healthy subjects. The circulating metabolite was devoid of any significant pharmacological activity 9.
- Route of elimination
Less than 4% of an orally administered dose is excreted unchanged in the urine due to extensive hepatic metabolism 11.
- Half-life
Following administration of a single intravenous dose of 100 mg over 10 minutes in adults with chronic bronchitis, the elimination half life of doxofylline was 1.83 ± 0.37 hours. Following oral administration of 400 mg twice daily for 5 days in adults with chronic bronchitis, the mean elimination half life was 7.01 ± 0.80 hours 9.
- Clearance
Following oral administration of 400 mg doxofylline twice daily for 5 days, the total clearance was 555.2 ± 180.6 mL/min 9.
- Adverse Effects
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Oral LD50 in rat and mouse are 965 mg/kg and 841 mg/kg, respectively. Intraperitoneal LD50 in rat and mouse are 426 mg/kg and 396 mg/kg, respectively MSDS.
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">
- Not Available
Interactions
- Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">
- 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.
Drug Interaction Integrate drug-drug
interactions in your software1,2-Benzodiazepine The therapeutic efficacy of 1,2-Benzodiazepine can be decreased when used in combination with Doxofylline. Abaloparatide The risk or severity of hypotension can be increased when Doxofylline is combined with Abaloparatide. Abametapir The serum concentration of Doxofylline can be increased when it is combined with Abametapir. Abatacept The metabolism of Doxofylline can be increased when combined with Abatacept. Abiraterone The serum concentration of Doxofylline can be increased when it is combined with Abiraterone. - Food Interactions
- Not Available
Products
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- International/Other Brands
- Ansimar (ABC Farmaceutici S.P.A) / Maxivent (Ajanta Pharma)
- Mixture Products
Name Ingredients Dosage Route Labeller Marketing Start Marketing End Region Image MUCOFIX 1200/400 MG EFERVESAN TABLET, 10 ADET Doxofylline (400 mg) + Acetylcysteine (1200 mg) Tablet, effervescent Oral NEUTEC İLAÇ SAN. TİC. A.Ş. 2011-07-26 Not applicable Turkey 
MUCOFIX 1200/400 MG EFERVESAN TABLET, 20 ADET Doxofylline (400 mg) + Acetylcysteine (1200 mg) Tablet, effervescent Oral NEUTEC İLAÇ SAN. TİC. A.Ş. 2011-07-26 Not applicable Turkey MUCOFIX 1200/400 MG EFERVESAN TABLET, 5 ADET Doxofylline (400 mg) + Acetylcysteine (1200 mg) Tablet, effervescent Oral NEUTEC İLAÇ SAN. TİC. A.Ş. 2011-07-26 Not applicable Turkey MUCOFIX 600/200 MG EFERVESAN, 10 ADET Doxofylline (200 mg) + Acetylcysteine (600 mg) Tablet, effervescent Oral NEUTEC İLAÇ SAN. TİC. A.Ş. 2011-07-26 Not applicable Turkey MUCOFIX 600/200 MG EFERVESAN, 20 ADET Doxofylline (200 mg) + Acetylcysteine (600 mg) Tablet, effervescent Oral NEUTEC İLAÇ SAN. TİC. A.Ş. 2011-07-26 Not applicable Turkey
Categories
- ATC Codes
- R03DA11 — Doxofylline
- Drug Categories
- Adrenergic Agonists
- Adrenergic beta-2 Receptor Agonists
- Adrenergic beta-Agonists
- Agents producing tachycardia
- Agents that produce hypertension
- Alkaloids
- Anti-Asthmatic Agents
- Antitussive Agents
- Autonomic Agents
- Bronchodilator Agents
- Central Nervous System Agents
- Cytochrome P-450 CYP1A2 Substrates
- Cytochrome P-450 Substrates
- Drugs for Obstructive Airway Diseases
- Enzyme Inhibitors
- Heterocyclic Compounds, Fused-Ring
- Peripheral Nervous System Agents
- Phosphodiesterase 5 Inhibitors
- Phosphodiesterase Inhibitors
- Purines
- Purinones
- Respiratory System Agents
- Vasodilating Agents
- Xanthine derivatives
- 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 / 1,3-dioxolanes / Heteroaromatic compounds / Ureas / Lactams / Oxacyclic compounds show 6 more
- Substituents
- 6-oxopurine / Acetal / Alkaloid or derivatives / Aromatic heteropolycyclic compound / Azacycle / Azole / Heteroaromatic compound / Hydrocarbon derivative / Imidazole / Lactam show 15 more
- Molecular Framework
- Aromatic heteropolycyclic compounds
- External Descriptors
- Not Available
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- MPM23GMO7Z
- CAS number
- 69975-86-6
- InChI Key
- HWXIGFIVGWUZAO-UHFFFAOYSA-N
- InChI
- InChI=1S/C11H14N4O4/c1-13-9-8(10(16)14(2)11(13)17)15(6-12-9)5-7-18-3-4-19-7/h6-7H,3-5H2,1-2H3
- IUPAC Name
- 7-[(1,3-dioxolan-2-yl)methyl]-1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione
- SMILES
- CN1C2=C(N(CC3OCCO3)C=N2)C(=O)N(C)C1=O
References
- General References
- Cirillo R, Barone D, Franzone JS: Doxofylline, an antiasthmatic drug lacking affinity for adenosine receptors. Arch Int Pharmacodyn Ther. 1988 Sep-Oct;295:221-37. [Article]
- Poggi R, Brandolese R, Bernasconi M, Manzin E, Rossi A: Doxofylline and respiratory mechanics. Short-term effects in mechanically ventilated patients with airflow obstruction and respiratory failure. Chest. 1989 Oct;96(4):772-8. [Article]
- Dini FL, Cogo R: Doxofylline: a new generation xanthine bronchodilator devoid of major cardiovascular adverse effects. Curr Med Res Opin. 2001;16(4):258-68. [Article]
- Sankar J, Lodha R, Kabra SK: Doxofylline: The next generation methylxanthine. Indian J Pediatr. 2008 Mar;75(3):251-4. [Article]
- Shukla D, Chakraborty S, Singh S, Mishra B: Doxofylline: a promising methylxanthine derivative for the treatment of asthma and chronic obstructive pulmonary disease. Expert Opin Pharmacother. 2009 Oct;10(14):2343-56. doi: 10.1517/14656560903200667. [Article]
- Matera MG, Page C, Cazzola M: Doxofylline is not just another theophylline! Int J Chron Obstruct Pulmon Dis. 2017 Dec 5;12:3487-3493. doi: 10.2147/COPD.S150887. eCollection 2017. [Article]
- van Mastbergen J, Jolas T, Allegra L, Page CP: The mechanism of action of doxofylline is unrelated to HDAC inhibition, PDE inhibition or adenosine receptor antagonism. Pulm Pharmacol Ther. 2012 Feb;25(1):55-61. doi: 10.1016/j.pupt.2011.10.007. Epub 2011 Nov 25. [Article]
- Zhang Y, Zeng K, Wang J, Gao H, Nan Y, Zheng X: Identifying the antiasthmatic target of doxofylline using immobilized beta2 -adrenoceptor based high-performance affinity chromatography and site-directed molecular docking. J Mol Recognit. 2016 Oct;29(10):492-8. doi: 10.1002/jmr.2549. Epub 2016 May 12. [Article]
- Doxofix Product Information [Link]
- Cayman Chemical Doxofylline Product Information [Link]
- Ansimar tablets Product Information [Link]
- External Links
- Human Metabolome Database
- HMDB0251602
- KEGG Drug
- D03898
- PubChem Compound
- 50942
- PubChem Substance
- 310265168
- ChemSpider
- 46175
- ChEBI
- 94714
- ChEMBL
- CHEMBL1527608
- ZINC
- ZINC000000003837
- PDBe Ligand
- 7UH
- Wikipedia
- Doxofylline
- PDB Entries
- 7vrz / 7vs0
- MSDS
- Download (24 KB)
Clinical Trials
- Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">
Phase Status Purpose Conditions Count 4 Completed Treatment Chronic Obstructive Pulmonary Disease (COPD) 1 4 Unknown Status Treatment Chronic Obstructive Pulmonary Disease (COPD) 1 3 Unknown Status Treatment Asthma in Children / Chronic Asthma 1 Not Available Completed Treatment Moderate to Severe Persistent Bronchial Asthma 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Capsule 300 MG Injection, solution Intravenous 100 MG/10ML Injection, solution Intravenous 300 mg/100ml Powder, for solution Oral 200 MG Syrup Oral 20 MG/ML Syrup Oral 2.000 g Solution Oral 2 g Granule, for solution Oral 200 MG Tablet Oral 800 mg Tablet, effervescent Injection, solution Intravenous 100 MG Syrup Oral 2 % Tablet, effervescent Oral Syrup Oral 2 g Syrup Oral 100 mg/5mL Tablet Oral 400 mg - Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Solid
- Experimental Properties
Property Value Source water solubility Insoluble MSDS - Predicted Properties
Property Value Source Water Solubility 14.5 mg/mL ALOGPS logP -0.94 ALOGPS logP -0.49 Chemaxon logS -1.3 ALOGPS pKa (Strongest Basic) -1.3 Chemaxon Physiological Charge 0 Chemaxon Hydrogen Acceptor Count 5 Chemaxon Hydrogen Donor Count 0 Chemaxon Polar Surface Area 76.9 Å2 Chemaxon Rotatable Bond Count 2 Chemaxon Refractivity 64.69 m3·mol-1 Chemaxon Polarizability 25.92 Å3 Chemaxon Number of Rings 3 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter No Chemaxon Veber's Rule No Chemaxon MDDR-like Rule No Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS splash10-014i-0090000000-d07591e502038035c3d6 Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS splash10-0670-1190000000-629c375138110e916440 Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS splash10-014i-1290000000-9eb010e5300882724b9a Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS splash10-07fr-0590000000-a47d03789fad5ad528b8 Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS splash10-00di-3290000000-5e10977f7d25cbc893d8 Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS splash10-0abi-3950000000-e07b70b2088753680c2f Predicted 1H NMR Spectrum 1D NMR Not Applicable Predicted 13C NMR Spectrum 1D NMR Not Applicable - Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 167.0761468 predictedDarkChem Lite v0.1.0 [M-H]- 161.16333 predictedDeepCCS 1.0 (2019) [M+H]+ 167.0929468 predictedDarkChem Lite v0.1.0 [M+H]+ 163.52133 predictedDeepCCS 1.0 (2019) [M+Na]+ 169.61449 predictedDeepCCS 1.0 (2019)
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Agonist
- General Function
- Protein homodimerization activity
- Specific Function
- Beta-adrenergic receptors mediate the catecholamine-induced activation of adenylate cyclase through the action of G proteins. The beta-2-adrenergic receptor binds epinephrine with an approximately ...
- Gene Name
- ADRB2
- Uniprot ID
- P07550
- Uniprot Name
- Beta-2 adrenergic receptor
- Molecular Weight
- 46458.32 Da
References
- Zhang Y, Zeng K, Wang J, Gao H, Nan Y, Zheng X: Identifying the antiasthmatic target of doxofylline using immobilized beta2 -adrenoceptor based high-performance affinity chromatography and site-directed molecular docking. J Mol Recognit. 2016 Oct;29(10):492-8. doi: 10.1002/jmr.2549. Epub 2016 May 12. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Antagonist
- Curator comments
- Reported antagonism of doxofyllin at adenosine A(2A) receptors was observed only at the highest tested concentration (10(-4) M).
- 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
- van Mastbergen J, Jolas T, Allegra L, Page CP: The mechanism of action of doxofylline is unrelated to HDAC inhibition, PDE inhibition or adenosine receptor antagonism. Pulm Pharmacol Ther. 2012 Feb;25(1):55-61. doi: 10.1016/j.pupt.2011.10.007. Epub 2011 Nov 25. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Tpr domain binding
- Specific Function
- Cyclic nucleotide phosphodiesterase with a dual-specificity for the second messengers cAMP and cGMP, which are key regulators of many important physiological processes.Isoform PDE2A2: Regulates Mit...
- Gene Name
- PDE2A
- Uniprot ID
- O00408
- Uniprot Name
- cGMP-dependent 3',5'-cyclic phosphodiesterase
- Molecular Weight
- 105715.85 Da
References
- van Mastbergen J, Jolas T, Allegra L, Page CP: The mechanism of action of doxofylline is unrelated to HDAC inhibition, PDE inhibition or adenosine receptor antagonism. Pulm Pharmacol Ther. 2012 Feb;25(1):55-61. doi: 10.1016/j.pupt.2011.10.007. Epub 2011 Nov 25. [Article]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- Curator comments
- This enzyme listing is based on pharmacokinetic data for methylxanthines as a drug class. Methylxanthines are metabolized by CYP1A2. This drug is a methylxanthine and is therefore assumed to be metabolized by this enzyme.
- 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
- Thorn CF, Aklillu E, McDonagh EM, Klein TE, Altman RB: PharmGKB summary: caffeine pathway. Pharmacogenet Genomics. 2012 May;22(5):389-95. doi: 10.1097/FPC.0b013e3283505d5e. [Article]
- Buters JT, Tang BK, Pineau T, Gelboin HV, Kimura S, Gonzalez FJ: Role of CYP1A2 in caffeine pharmacokinetics and metabolism: studies using mice deficient in CYP1A2. Pharmacogenetics. 1996 Aug;6(4):291-6. [Article]
- Hakooz NM: Caffeine metabolic ratios for the in vivo evaluation of CYP1A2, N-acetyltransferase 2, xanthine oxidase and CYP2A6 enzymatic activities. Curr Drug Metab. 2009 May;10(4):329-38. [Article]
- Rasmussen BB, Brosen K: Determination of urinary metabolites of caffeine for the assessment of cytochrome P4501A2, xanthine oxidase, and N-acetyltransferase activity in humans. Ther Drug Monit. 1996 Jun;18(3):254-62. [Article]
- Theophylline metabolic pathway [Link]
- CYP1A2 activity, gender and smoking, as variables influencing the toxicity of caffeine [File]
Drug created at October 28, 2015 20:04 / Updated at August 09, 2023 00:07