Identification

Name
Doxofylline
Accession Number
DB09273
Type
Small Molecule
Groups
Approved, Investigational
Description

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. Unlike other xanthines, doxofylline lacks any significant affinity for adenosine A1 or A2 receptors and does not produce stimulant effects. Decreased affinity for adenosine receptors may account for the better safety profile of doxofylline compared to theophylline [7]. 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.

Structure
Thumb
Synonyms
  • Doxophylline
External IDs
ABC 12/3
International/Other Brands
Ansimar (ABC Farmaceutici S.P.A) / Maxivent (Ajanta Pharma)
Categories
UNII
MPM23GMO7Z
CAS number
69975-86-6
Weight
Average: 266.257
Monoisotopic: 266.101504947
Chemical Formula
C11H14N4O4
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

Pharmacology

Indication

Indicated for the treatment of chronic obstructive pulmonary disease (COPD), bronchial asthma and pulmonary disease with spastic bronchial component.

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 [7].

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 [A31642]. 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 [A31646]. Serine 169 and serine 173 residues in the receptor are thought to be critical binding sites for doxofylline where hydrogen bonds are formed [A31646]. 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 [A31646]. 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
APhosphodiesterase 2A, cGMP-stimulated
inhibitor
Human
UAdenosine receptor A2a
antagonist
Human
ABeta-2 adrenergic receptor
agonist
Human
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 [7]. The absolute bioavailability of doxofylline in healthy subjects was 63 ± 25% [7].

Volume of distribution

Doxofylline demonstrates a short distribution phase following intravenous administration of 100 mg given in adults with chronic bronchitis [7]. As methylxanthines are distributed to all body compartments, doxofylline may be detected in breast milk and placenta [7].

Protein binding

At pH 7.4, the fraction of plasma protein binding is about 48% [9].

Metabolism

Doxofylline is thought to undergo hepatic metabolism which accounts for 90% of total drug clearance [9]. 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 [7].

Route of elimination

Less than 4% of an orally administered dose is excreted unchanged in the urine due to extensive hepatic metabolism [9].

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 [7].

Clearance

Following oral administration of 400 mg doxofylline twice daily for 5 days, the total clearance was 555.2 ± 180.6 mL/min [7].

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].

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
7-NitroindazoleThe serum concentration of Doxofylline can be decreased when it is combined with 7-Nitroindazole.
7,8-Dichloro-1,2,3,4-tetrahydroisoquinolineThe risk or severity of adverse effects can be increased when 7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline is combined with Doxofylline.
AbediterolThe risk or severity of adverse effects can be increased when Doxofylline is combined with Abediterol.
AcebutololThe therapeutic efficacy of Doxofylline can be decreased when used in combination with Acebutolol.
AcenocoumarolThe serum concentration of Doxofylline can be increased when it is combined with Acenocoumarol.
AcepromazineAcepromazine may decrease the vasoconstricting activities of Doxofylline.
AcetaminophenThe serum concentration of Doxofylline can be increased when it is combined with Acetaminophen.
AcetazolamideThe serum concentration of Doxofylline can be decreased when it is combined with Acetazolamide.
AdalimumabThe serum concentration of Doxofylline can be decreased when it is combined with Adalimumab.
AdenosineThe therapeutic efficacy of Adenosine can be decreased when used in combination with Doxofylline.
Food Interactions
Not Available

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. [PubMed:3245738]
  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. [PubMed:2791671]
  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. [PubMed:11268710]
  4. Sankar J, Lodha R, Kabra SK: Doxofylline: The next generation methylxanthine. Indian J Pediatr. 2008 Mar;75(3):251-4. [PubMed:18376093]
  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. [PubMed:19678793]
  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. [PubMed:29255355]
  7. Doxofix Product Information [Link]
  8. Cayman Chemical Doxofylline Product Information [Link]
  9. Ansimar tablets Product Information [Link]
External Links
KEGG Drug
D03898
PubChem Compound
50942
PubChem Substance
310265168
ChemSpider
46175
ChEBI
94714
ChEMBL
CHEMBL1527608
Wikipedia
Doxofylline
ATC Codes
R03DA11 — DoxofyllineR03DA20 — Combinations of xanthines
MSDS
Download (24 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4Not Yet RecruitingTreatmentChronic Obstructive Pulmonary Disease (COPD)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
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/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

Taxonomy

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
Xanthine / 6-oxopurine / Purinone / Alkaloid or derivatives / Pyrimidone / N-substituted imidazole / Pyrimidine / Meta-dioxolane / Azole / Imidazole
show 15 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Metal ion binding
Specific Function
Not Available
Gene Name
PDE2A
Uniprot ID
Q8IW54
Uniprot Name
Phosphodiesterase 2A, cGMP-stimulated
Molecular Weight
105647.74 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. [PubMed:22138191]
Kind
Protein
Organism
Human
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. [PubMed:22138191]
Kind
Protein
Organism
Human
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. [PubMed:27173639]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
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

Drug created on October 28, 2015 14:04 / Updated on August 18, 2018 15:02