Doxofylline

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
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.

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Used in combination to treatBronchial asthmaCombination Product in combination with: Acetylcysteine (DB06151)••••••••••••••••••• ••••••••••••
Treatment ofBronchial asthma••••••••••••••••••• ••••••••••••
Treatment ofBronchial asthma•••••••••••••••••••• ••• ••••••••• •••••••••• ••••••••• ••••••• ••• ••••••••• •••••• ••••••
Used in combination to treatChronic obstructive pulmonary disease (copd)Combination Product in combination with: Acetylcysteine (DB06151)••••••••••••••••••• ••••••••••••
Treatment ofChronic obstructive pulmonary disease (copd)••••••••••••••••••• ••••••••••••
Contraindications & Blackbox Warnings
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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.

TargetActionsOrganism
ABeta-2 adrenergic receptor
agonist
Humans
UAdenosine receptor A2a
antagonist
Humans
AcGMP-dependent 3',5'-cyclic phosphodiesterase
inhibitor
Humans
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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Toxicity

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
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
1,2-BenzodiazepineThe therapeutic efficacy of 1,2-Benzodiazepine can be decreased when used in combination with Doxofylline.
AbaloparatideThe risk or severity of hypotension can be increased when Doxofylline is combined with Abaloparatide.
AbametapirThe serum concentration of Doxofylline can be increased when it is combined with Abametapir.
AbataceptThe metabolism of Doxofylline can be increased when combined with Abatacept.
AbirateroneThe serum concentration of Doxofylline can be increased when it is combined with Abiraterone.
Food Interactions
Not Available

Products

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International/Other Brands
Ansimar (ABC Farmaceutici S.P.A) / Maxivent (Ajanta Pharma)
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
MUCOFIX 1200/400 MG EFERVESAN TABLET, 10 ADETDoxofylline (400 mg) + Acetylcysteine (1200 mg)Tablet, effervescentOralNEUTEC İLAÇ SAN. TİC. A.Ş.2011-07-26Not applicableTurkey flag
MUCOFIX 1200/400 MG EFERVESAN TABLET, 20 ADETDoxofylline (400 mg) + Acetylcysteine (1200 mg)Tablet, effervescentOralNEUTEC İLAÇ SAN. TİC. A.Ş.2011-07-26Not applicableTurkey flag
MUCOFIX 1200/400 MG EFERVESAN TABLET, 5 ADETDoxofylline (400 mg) + Acetylcysteine (1200 mg)Tablet, effervescentOralNEUTEC İLAÇ SAN. TİC. A.Ş.2011-07-26Not applicableTurkey flag
MUCOFIX 600/200 MG EFERVESAN, 10 ADETDoxofylline (200 mg) + Acetylcysteine (600 mg)Tablet, effervescentOralNEUTEC İLAÇ SAN. TİC. A.Ş.2011-07-26Not applicableTurkey flag
MUCOFIX 600/200 MG EFERVESAN, 20 ADETDoxofylline (200 mg) + Acetylcysteine (600 mg)Tablet, effervescentOralNEUTEC İLAÇ SAN. TİC. A.Ş.2011-07-26Not applicableTurkey flag

Categories

ATC Codes
R03DA11 — Doxofylline
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 / 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
  1. 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]
  2. 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]
  3. 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]
  4. Sankar J, Lodha R, Kabra SK: Doxofylline: The next generation methylxanthine. Indian J Pediatr. 2008 Mar;75(3):251-4. [Article]
  5. 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]
  6. 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]
  7. 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]
  8. 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]
  9. Doxofix Product Information [Link]
  10. Cayman Chemical Doxofylline Product Information [Link]
  11. Ansimar tablets Product Information [Link]
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
PhaseStatusPurposeConditionsCount
4CompletedTreatmentChronic Obstructive Pulmonary Disease (COPD)1
4Unknown StatusTreatmentChronic Obstructive Pulmonary Disease (COPD)1
3Unknown StatusTreatmentAsthma in Children / Chronic Asthma1
Not AvailableCompletedTreatmentModerate to Severe Persistent Bronchial Asthma1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Capsule300 MG
Injection, solutionIntravenous100 MG/10ML
Injection, solutionIntravenous300 mg/100ml
Powder, for solutionOral200 MG
SyrupOral20 MG/ML
SyrupOral2.000 g
TabletOral400.000 mg
SolutionOral2 g
Granule, for solutionOral200 MG
TabletOral800 mg
Tablet, effervescent
Injection, solutionIntravenous100 MG
SyrupOral2 %
Tablet, effervescentOral
SyrupOral2 g
SyrupOral100 mg/5mL
TabletOral400 mg
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubilityInsolubleMSDS
Predicted Properties
PropertyValueSource
Water Solubility14.5 mg/mLALOGPS
logP-0.94ALOGPS
logP-0.49Chemaxon
logS-1.3ALOGPS
pKa (Strongest Basic)-1.3Chemaxon
Physiological Charge0Chemaxon
Hydrogen Acceptor Count5Chemaxon
Hydrogen Donor Count0Chemaxon
Polar Surface Area76.9 Å2Chemaxon
Rotatable Bond Count2Chemaxon
Refractivity64.69 m3·mol-1Chemaxon
Polarizability25.92 Å3Chemaxon
Number of Rings3Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterNoChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleNoChemaxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-014i-0090000000-d07591e502038035c3d6
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-0670-1190000000-629c375138110e916440
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-014i-1290000000-9eb010e5300882724b9a
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-07fr-0590000000-a47d03789fad5ad528b8
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-00di-3290000000-5e10977f7d25cbc893d8
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-0abi-3950000000-e07b70b2088753680c2f
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-167.0761468
predicted
DarkChem Lite v0.1.0
[M-H]-161.16333
predicted
DeepCCS 1.0 (2019)
[M+H]+167.0929468
predicted
DarkChem Lite v0.1.0
[M+H]+163.52133
predicted
DeepCCS 1.0 (2019)
[M+Na]+169.61449
predicted
DeepCCS 1.0 (2019)

Targets

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insights and accelerate drug research.
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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
  1. 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
  1. 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
  1. 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
  1. 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]
  2. 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]
  3. 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]
  4. 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]
  5. Theophylline metabolic pathway [Link]
  6. 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