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
DrugInteractionDrug group
7-NitroindazoleThe serum concentration of Doxofylline can be decreased when it is combined with 7-Nitroindazole.Experimental
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.Experimental
AbediterolThe risk or severity of adverse effects can be increased when Doxofylline is combined with Abediterol.Investigational
AcebutololThe risk or severity of adverse effects can be increased when Acebutolol is combined with Doxofylline.Approved, Investigational
AcepromazineAcepromazine may decrease the vasoconstricting activities of Doxofylline.Approved, Vet Approved
AcetazolamideThe serum concentration of Doxofylline can be decreased when it is combined with Acetazolamide.Approved, Vet Approved
AlfuzosinAlfuzosin may decrease the vasoconstricting activities of Doxofylline.Approved, Investigational
AllopurinolThe serum concentration of Doxofylline can be increased when it is combined with Allopurinol.Approved
AlprenololAlprenolol may decrease the bronchodilatory activities of Doxofylline.Approved, Withdrawn
Ambroxol acefyllinateThe risk or severity of adverse effects can be increased when Ambroxol acefyllinate is combined with Doxofylline.Experimental, Investigational
AmineptineThe risk or severity of adverse effects can be increased when Amineptine is combined with Doxofylline.Illicit, Withdrawn
AminophyllineThe risk or severity of adverse effects can be increased when Aminophylline is combined with Doxofylline.Approved
AmitriptylineThe risk or severity of adverse effects can be increased when Amitriptyline is combined with Doxofylline.Approved
AmitriptylinoxideThe risk or severity of adverse effects can be increased when Amitriptylinoxide is combined with Doxofylline.Approved, Investigational
AmoxapineThe risk or severity of adverse effects can be increased when Amoxapine is combined with Doxofylline.Approved
AmphetamineThe risk or severity of adverse effects can be increased when Amphetamine is combined with Doxofylline.Approved, Illicit, Investigational
Anthranilic acidThe serum concentration of Doxofylline can be decreased when it is combined with Anthranilic acid.Experimental
ArbutamineThe risk or severity of adverse effects can be increased when Doxofylline is combined with Arbutamine.Approved
ArformoterolThe risk or severity of adverse effects can be increased when Doxofylline is combined with Arformoterol.Approved, Investigational
AripiprazoleAripiprazole may decrease the vasoconstricting activities of Doxofylline.Approved, Investigational
AsenapineAsenapine may decrease the vasoconstricting activities of Doxofylline.Approved
AtenololAtenolol may decrease the bronchodilatory activities of Doxofylline.Approved
AtomoxetineAtomoxetine may increase the tachycardic activities of Doxofylline.Approved
AtosibanThe risk or severity of adverse effects can be increased when Doxofylline is combined with Atosiban.Approved, Investigational
AzosemideDoxofylline may increase the hypokalemic activities of Azosemide.Investigational
BambuterolThe risk or severity of adverse effects can be increased when Doxofylline is combined with Bambuterol.Approved, Investigational
BarbexacloneThe serum concentration of Doxofylline can be decreased when it is combined with Barbexaclone.Experimental
BeclamideThe serum concentration of Doxofylline can be decreased when it is combined with Beclamide.Experimental
BendroflumethiazideDoxofylline may increase the hypokalemic activities of Bendroflumethiazide.Approved
BenmoxinThe risk or severity of adverse effects can be increased when Benmoxin is combined with Doxofylline.Withdrawn
BenzphetamineThe risk or severity of adverse effects can be increased when Benzphetamine is combined with Doxofylline.Approved, Illicit
BenzthiazideDoxofylline may increase the hypokalemic activities of Benzthiazide.Approved
Benzylpenicilloyl PolylysineDoxofylline may decrease effectiveness of Benzylpenicilloyl Polylysine as a diagnostic agent.Approved
BetahistineThe therapeutic efficacy of Doxofylline can be decreased when used in combination with Betahistine.Approved, Investigational
BetaxololBetaxolol may decrease the bronchodilatory activities of Doxofylline.Approved, Investigational
BevantololBevantolol may decrease the vasoconstricting activities of Doxofylline.Approved
BisoprololBisoprolol may decrease the bronchodilatory activities of Doxofylline.Approved
BitolterolThe risk or severity of adverse effects can be increased when Doxofylline is combined with Bitolterol.Withdrawn
BopindololBopindolol may decrease the bronchodilatory activities of Doxofylline.Approved
BrexpiprazoleBrexpiprazole may decrease the vasoconstricting activities of Doxofylline.Approved, Investigational
BrivaracetamThe serum concentration of Doxofylline can be decreased when it is combined with Brivaracetam.Approved, Investigational
BrofaromineThe risk or severity of adverse effects can be increased when Brofaromine is combined with Doxofylline.Experimental
BromocriptineBromocriptine may increase the hypertensive and vasoconstricting activities of Doxofylline.Approved, Investigational
BucindololThe risk or severity of adverse effects can be increased when Bucindolol is combined with Doxofylline.Investigational
BumetanideDoxofylline may increase the hypokalemic activities of Bumetanide.Approved
BunazosinBunazosin may decrease the vasoconstricting activities of Doxofylline.Investigational
BupranololBupranolol may decrease the bronchodilatory activities of Doxofylline.Approved
ButriptylineThe risk or severity of adverse effects can be increased when Butriptyline is combined with Doxofylline.Approved
CabergolineCabergoline may increase the hypertensive and vasoconstricting activities of Doxofylline.Approved
CaffeineThe risk or severity of adverse effects can be increased when Caffeine is combined with Doxofylline.Approved
CarbamazepineThe serum concentration of Doxofylline can be decreased when it is combined with Carbamazepine.Approved, Investigational
CarisbamateThe serum concentration of Doxofylline can be decreased when it is combined with Carisbamate.Investigational
CaroxazoneThe risk or severity of adverse effects can be increased when Caroxazone is combined with Doxofylline.Withdrawn
CarteololCarteolol may decrease the bronchodilatory activities of Doxofylline.Approved
CarvedilolCarvedilol may decrease the vasoconstricting activities of Doxofylline.Approved, Investigational
CeliprololThe risk or severity of adverse effects can be increased when Doxofylline is combined with Celiprolol.Approved, Investigational
ChlorothiazideDoxofylline may increase the hypokalemic activities of Chlorothiazide.Approved, Vet Approved
ChlorphentermineThe risk or severity of adverse effects can be increased when Chlorphentermine is combined with Doxofylline.Illicit, Withdrawn
ChlorpromazineChlorpromazine may decrease the vasoconstricting activities of Doxofylline.Approved, Investigational, Vet Approved
ChlorthalidoneDoxofylline may increase the hypokalemic activities of Chlorthalidone.Approved
CimetidineThe serum concentration of Doxofylline can be increased when it is combined with Cimetidine.Approved, Investigational
ClenbuterolThe risk or severity of adverse effects can be increased when Doxofylline is combined with Clenbuterol.Approved, Investigational, Vet Approved
ClobazamThe serum concentration of Doxofylline can be decreased when it is combined with Clobazam.Approved, Illicit
clomethiazoleThe serum concentration of Doxofylline can be decreased when it is combined with clomethiazole.Investigational
ClomipramineThe risk or severity of adverse effects can be increased when Clomipramine is combined with Doxofylline.Approved, Investigational, Vet Approved
ClonazepamThe serum concentration of Doxofylline can be decreased when it is combined with Clonazepam.Approved, Illicit
CloranololCloranolol may decrease the bronchodilatory activities of Doxofylline.Experimental
ClorazepateThe serum concentration of Doxofylline can be decreased when it is combined with Clorazepate.Approved, Illicit
ClozapineClozapine may decrease the vasoconstricting activities of Doxofylline.Approved
CyclopenthiazideDoxofylline may increase the hypokalemic activities of Cyclopenthiazide.Experimental
DapiprazoleDapiprazole may decrease the vasoconstricting activities of Doxofylline.Approved
DelorazepamThe serum concentration of Doxofylline can be decreased when it is combined with Delorazepam.Approved, Illicit, Investigational
DeramciclaneThe serum concentration of Doxofylline can be decreased when it is combined with Deramciclane.Investigational
DesipramineThe risk or severity of adverse effects can be increased when Desipramine is combined with Doxofylline.Approved, Investigational
DesvenlafaxineDesvenlafaxine may increase the tachycardic activities of Doxofylline.Approved, Investigational
DextroamphetamineDextroamphetamine may decrease the vasoconstricting activities of Doxofylline.Approved, Illicit
DiazepamThe serum concentration of Doxofylline can be decreased when it is combined with Diazepam.Approved, Illicit, Investigational, Vet Approved
DibenzepinThe risk or severity of adverse effects can be increased when Dibenzepin is combined with Doxofylline.Experimental
DihydroergotamineDihydroergotamine may increase the hypertensive and vasoconstricting activities of Doxofylline.Approved, Investigational
DimetacrineThe risk or severity of adverse effects can be increased when Dimetacrine is combined with Doxofylline.Approved, Withdrawn
DipivefrinThe risk or severity of adverse effects can be increased when Doxofylline is combined with Dipivefrin.Approved
DobutamineThe risk or severity of adverse effects can be increased when Doxofylline is combined with Dobutamine.Approved
DopamineThe risk or severity of adverse effects can be increased when Dopamine is combined with Doxofylline.Approved
DoramectinThe serum concentration of Doxofylline can be decreased when it is combined with Doramectin.Vet Approved
DosulepinThe risk or severity of adverse effects can be increased when Dosulepin is combined with Doxofylline.Approved
DoxazosinDoxazosin may decrease the vasoconstricting activities of Doxofylline.Approved
DoxepinThe risk or severity of adverse effects can be increased when Doxepin is combined with Doxofylline.Approved, Investigational
DronedaroneDronedarone may decrease the vasoconstricting activities of Doxofylline.Approved
DroperidolDroperidol may decrease the vasoconstricting activities of Doxofylline.Approved, Vet Approved
DroxidopaThe risk or severity of adverse effects can be increased when Doxofylline is combined with Droxidopa.Approved, Investigational
DuloxetineDuloxetine may increase the tachycardic activities of Doxofylline.Approved
DyphyllineThe risk or severity of adverse effects can be increased when Dyphylline is combined with Doxofylline.Approved
EpanololThe risk or severity of adverse effects can be increased when Epanolol is combined with Doxofylline.Experimental
EperisoneThe serum concentration of Doxofylline can be decreased when it is combined with Eperisone.Approved, Investigational
EphedraThe risk or severity of adverse effects can be increased when Doxofylline is combined with Ephedra.Approved, Nutraceutical, Withdrawn
EphedrineThe risk or severity of adverse effects can be increased when Ephedrine is combined with Doxofylline.Approved
EpinephrineThe risk or severity of adverse effects can be increased when Doxofylline is combined with Epinephrine.Approved, Vet Approved
EpitizideDoxofylline may increase the hypokalemic activities of Epitizide.Experimental
Ergoloid mesylateErgoloid mesylate may increase the hypertensive and vasoconstricting activities of Doxofylline.Approved
ErgonovineErgonovine may increase the hypertensive and vasoconstricting activities of Doxofylline.Approved
ErgotamineErgotamine may increase the hypertensive and vasoconstricting activities of Doxofylline.Approved
ErythromycinThe serum concentration of Doxofylline can be increased when it is combined with Erythromycin.Approved, Investigational, Vet Approved
EscitalopramEscitalopram may decrease the vasoconstricting activities of Doxofylline.Approved, Investigational
Eslicarbazepine acetateThe serum concentration of Doxofylline can be decreased when it is combined with Eslicarbazepine acetate.Approved
EsmololEsmolol may decrease the bronchodilatory activities of Doxofylline.Approved
EstazolamThe serum concentration of Doxofylline can be decreased when it is combined with Estazolam.Approved, Illicit
Etacrynic acidDoxofylline may increase the hypokalemic activities of Etacrynic acid.Approved, Investigational
EtafedrineThe risk or severity of adverse effects can be increased when Doxofylline is combined with Etafedrine.Approved
EthadioneThe serum concentration of Doxofylline can be decreased when it is combined with Ethadione.Experimental
EthosuximideThe serum concentration of Doxofylline can be decreased when it is combined with Ethosuximide.Approved
EthotoinThe serum concentration of Doxofylline can be decreased when it is combined with Ethotoin.Approved
EtilefrineThe risk or severity of adverse effects can be increased when Etilefrine is combined with Doxofylline.Withdrawn
EtiracetamThe serum concentration of Doxofylline can be decreased when it is combined with Etiracetam.Investigational
EzogabineThe serum concentration of Doxofylline can be decreased when it is combined with Ezogabine.Approved, Investigational
FelbamateThe serum concentration of Doxofylline can be decreased when it is combined with Felbamate.Approved
FenoterolThe risk or severity of adverse effects can be increased when Doxofylline is combined with Fenoterol.Approved, Investigational
FenozoloneThe risk or severity of adverse effects can be increased when Fenozolone is combined with Doxofylline.Experimental
FludiazepamThe serum concentration of Doxofylline can be decreased when it is combined with Fludiazepam.Approved, Illicit
FlunarizineThe serum concentration of Doxofylline can be decreased when it is combined with Flunarizine.Approved
FlupentixolFlupentixol may decrease the vasoconstricting activities of Doxofylline.Approved, Investigational, Withdrawn
FormoterolThe risk or severity of adverse effects can be increased when Doxofylline is combined with Formoterol.Approved, Investigational
FosphenytoinThe serum concentration of Doxofylline can be decreased when it is combined with Fosphenytoin.Approved, Investigational
FurazolidoneThe risk or severity of adverse effects can be increased when Furazolidone is combined with Doxofylline.Approved, Investigational, Vet Approved
FurosemideDoxofylline may increase the hypokalemic activities of Furosemide.Approved, Vet Approved
GabapentinThe serum concentration of Doxofylline can be decreased when it is combined with Gabapentin.Approved, Investigational
GaboxadolThe serum concentration of Doxofylline can be decreased when it is combined with Gaboxadol.Investigational
HarmalineThe risk or severity of adverse effects can be increased when Harmaline is combined with Doxofylline.Experimental
HexoprenalineThe risk or severity of adverse effects can be increased when Doxofylline is combined with Hexoprenaline.Approved, Withdrawn
HydracarbazineThe risk or severity of adverse effects can be increased when Hydracarbazine is combined with Doxofylline.Experimental
HydrochlorothiazideDoxofylline may increase the hypokalemic activities of Hydrochlorothiazide.Approved, Vet Approved
HydroflumethiazideDoxofylline may increase the hypokalemic activities of Hydroflumethiazide.Approved, Investigational
HydroxyamphetamineThe risk or severity of adverse effects can be increased when Hydroxyamphetamine is combined with Doxofylline.Approved
IfenprodilThe serum concentration of Doxofylline can be decreased when it is combined with Ifenprodil.Approved, Investigational, Withdrawn
IloperidoneIloperidone may decrease the vasoconstricting activities of Doxofylline.Approved
ImipramineThe risk or severity of adverse effects can be increased when Imipramine is combined with Doxofylline.Approved
IndacaterolThe risk or severity of adverse effects can be increased when Doxofylline is combined with Indacaterol.Approved
IndapamideDoxofylline may increase the hypokalemic activities of Indapamide.Approved
IndoraminIndoramin may decrease the vasoconstricting activities of Doxofylline.Withdrawn
IprindoleThe risk or severity of adverse effects can be increased when Iprindole is combined with Doxofylline.Experimental
IproclozideThe risk or severity of adverse effects can be increased when Iproclozide is combined with Doxofylline.Withdrawn
IproniazidThe risk or severity of adverse effects can be increased when Iproniazid is combined with Doxofylline.Withdrawn
IsocarboxazidThe risk or severity of adverse effects can be increased when Isocarboxazid is combined with Doxofylline.Approved
IsoetarineThe risk or severity of adverse effects can be increased when Doxofylline is combined with Isoetarine.Approved
IsoprenalineThe risk or severity of adverse effects can be increased when Doxofylline is combined with Isoprenaline.Approved, Investigational
IsoxsuprineThe risk or severity of adverse effects can be increased when Isoxsuprine is combined with Doxofylline.Approved, Withdrawn
LabetalolThe risk or severity of adverse effects can be increased when Labetalol is combined with Doxofylline.Approved
LacosamideThe serum concentration of Doxofylline can be decreased when it is combined with Lacosamide.Approved
LamotrigineThe serum concentration of Doxofylline can be decreased when it is combined with Lamotrigine.Approved, Investigational
LevetiracetamThe serum concentration of Doxofylline can be decreased when it is combined with Levetiracetam.Approved, Investigational
LevomilnacipranLevomilnacipran may increase the tachycardic activities of Doxofylline.Approved, Investigational
LevosalbutamolThe risk or severity of adverse effects can be increased when Doxofylline is combined with Levosalbutamol.Approved, Investigational
LincomycinThe serum concentration of Doxofylline can be increased when it is combined with Lincomycin.Approved, Vet Approved
LisdexamfetamineLisdexamfetamine may decrease the vasoconstricting activities of Doxofylline.Approved, Investigational
LofepramineThe risk or severity of adverse effects can be increased when Lofepramine is combined with Doxofylline.Experimental
LorazepamThe serum concentration of Doxofylline can be decreased when it is combined with Lorazepam.Approved
Magnesium sulfateThe serum concentration of Doxofylline can be decreased when it is combined with Magnesium sulfate.Approved, Investigational, Vet Approved
MebanazineThe risk or severity of adverse effects can be increased when Mebanazine is combined with Doxofylline.Withdrawn
MebeverineThe serum concentration of Doxofylline can be decreased when it is combined with Mebeverine.Approved, Investigational
MedazepamThe serum concentration of Doxofylline can be decreased when it is combined with Medazepam.Experimental
MefenorexThe risk or severity of adverse effects can be increased when Mefenorex is combined with Doxofylline.Experimental
MelitracenThe risk or severity of adverse effects can be increased when Melitracen is combined with Doxofylline.Experimental, Investigational
MephentermineThe risk or severity of adverse effects can be increased when Mephentermine is combined with Doxofylline.Approved
MephenytoinThe serum concentration of Doxofylline can be decreased when it is combined with Mephenytoin.Investigational, Withdrawn
MepindololMepindolol may decrease the bronchodilatory activities of Doxofylline.Experimental
MeprobamateThe serum concentration of Doxofylline can be decreased when it is combined with Meprobamate.Approved, Illicit
MetaraminolThe risk or severity of adverse effects can be increased when Metaraminol is combined with Doxofylline.Approved, Investigational
MethamphetamineThe risk or severity of adverse effects can be increased when Methamphetamine is combined with Doxofylline.Approved, Illicit
MetharbitalThe serum concentration of Doxofylline can be decreased when it is combined with Metharbital.Withdrawn
MethotrimeprazineMethotrimeprazine may decrease the vasoconstricting activities of Doxofylline.Approved, Investigational
MethoxamineThe risk or severity of adverse effects can be increased when Methoxamine is combined with Doxofylline.Approved, Investigational
MethsuximideThe serum concentration of Doxofylline can be decreased when it is combined with Methsuximide.Approved
MethyclothiazideDoxofylline may increase the hypokalemic activities of Methyclothiazide.Approved
Methylene blueThe risk or severity of adverse effects can be increased when Methylene blue is combined with Doxofylline.Approved, Investigational
MethylergometrineMethylergometrine may increase the hypertensive and vasoconstricting activities of Doxofylline.Approved
MethylphenobarbitalThe serum concentration of Doxofylline can be decreased when it is combined with Methylphenobarbital.Approved
MetolazoneDoxofylline may increase the hypokalemic activities of Metolazone.Approved
MetoprololMetoprolol may decrease the bronchodilatory activities of Doxofylline.Approved, Investigational
MidodrineThe risk or severity of adverse effects can be increased when Midodrine is combined with Doxofylline.Approved
MilnacipranMilnacipran may increase the tachycardic activities of Doxofylline.Approved, Investigational
MinaprineThe risk or severity of adverse effects can be increased when Minaprine is combined with Doxofylline.Approved
MK-212The serum concentration of Doxofylline can be decreased when it is combined with MK-212.Investigational
MoclobemideThe risk or severity of adverse effects can be increased when Moclobemide is combined with Doxofylline.Approved, Investigational
NadololNadolol may decrease the bronchodilatory activities of Doxofylline.Approved
NebivololNebivolol may decrease the bronchodilatory activities of Doxofylline.Approved, Investigational
NefazodoneNefazodone may decrease the vasoconstricting activities of Doxofylline.Approved, Withdrawn
NeocitrullamonThe serum concentration of Doxofylline can be decreased when it is combined with Neocitrullamon.Experimental
NialamideThe risk or severity of adverse effects can be increased when Nialamide is combined with Doxofylline.Withdrawn
NicardipineNicardipine may decrease the vasoconstricting activities of Doxofylline.Approved, Investigational
NicergolineNicergoline may decrease the vasoconstricting activities of Doxofylline.Approved, Investigational
NiguldipineNiguldipine may decrease the vasoconstricting activities of Doxofylline.Experimental
NitrazepamThe serum concentration of Doxofylline can be decreased when it is combined with Nitrazepam.Approved
NorepinephrineThe risk or severity of adverse effects can be increased when Doxofylline is combined with Norepinephrine.Approved
NortriptylineThe risk or severity of adverse effects can be increased when Nortriptyline is combined with Doxofylline.Approved
NylidrinThe risk or severity of adverse effects can be increased when Nylidrin is combined with Doxofylline.Approved
OctamoxinThe risk or severity of adverse effects can be increased when Octamoxin is combined with Doxofylline.Withdrawn
OlanzapineOlanzapine may decrease the vasoconstricting activities of Doxofylline.Approved, Investigational
OlodaterolThe risk or severity of adverse effects can be increased when Doxofylline is combined with Olodaterol.Approved
OpipramolThe risk or severity of adverse effects can be increased when Opipramol is combined with Doxofylline.Investigational
OrciprenalineThe risk or severity of adverse effects can be increased when Doxofylline is combined with Orciprenaline.Approved
OxcarbazepineThe serum concentration of Doxofylline can be decreased when it is combined with Oxcarbazepine.Approved
OxprenololOxprenolol may decrease the bronchodilatory activities of Doxofylline.Approved
OxymetazolineThe risk or severity of adverse effects can be increased when Oxymetazoline is combined with Doxofylline.Approved, Investigational
PaliperidonePaliperidone may decrease the vasoconstricting activities of Doxofylline.Approved
ParaldehydeThe serum concentration of Doxofylline can be decreased when it is combined with Paraldehyde.Approved, Investigational
ParamethadioneThe serum concentration of Doxofylline can be decreased when it is combined with Paramethadione.Approved
PargylineThe risk or severity of adverse effects can be increased when Pargyline is combined with Doxofylline.Approved
PenbutololPenbutolol may decrease the bronchodilatory activities of Doxofylline.Approved, Investigational
PerampanelThe serum concentration of Doxofylline can be decreased when it is combined with Perampanel.Approved
PF-00610355The risk or severity of adverse effects can be increased when Doxofylline is combined with PF-00610355.Investigational
PhenacemideThe serum concentration of Doxofylline can be decreased when it is combined with Phenacemide.Approved
PhenelzineThe risk or severity of adverse effects can be increased when Phenelzine is combined with Doxofylline.Approved
PheneturideThe serum concentration of Doxofylline can be decreased when it is combined with Pheneturide.Experimental
PhenibutThe serum concentration of Doxofylline can be decreased when it is combined with Phenibut.Experimental
PheniprazineThe risk or severity of adverse effects can be increased when Pheniprazine is combined with Doxofylline.Withdrawn
PhenmetrazineThe risk or severity of adverse effects can be increased when Phenmetrazine is combined with Doxofylline.Approved, Illicit
PhenobarbitalThe serum concentration of Doxofylline can be decreased when it is combined with Phenobarbital.Approved, Investigational
PhenoxybenzaminePhenoxybenzamine may decrease the vasoconstricting activities of Doxofylline.Approved
PhenoxypropazineThe risk or severity of adverse effects can be increased when Phenoxypropazine is combined with Doxofylline.Withdrawn
PhensuximideThe serum concentration of Doxofylline can be decreased when it is combined with Phensuximide.Approved
PhentermineThe risk or severity of adverse effects can be increased when Phentermine is combined with Doxofylline.Approved, Illicit
PhentolaminePhentolamine may decrease the vasoconstricting activities of Doxofylline.Approved
PhenylephrineThe risk or severity of adverse effects can be increased when Phenylephrine is combined with Doxofylline.Approved
PhenylpropanolamineThe risk or severity of adverse effects can be increased when Doxofylline is combined with Phenylpropanolamine.Approved, Vet Approved, Withdrawn
PhenytoinThe serum concentration of Doxofylline can be decreased when it is combined with Phenytoin.Approved, Vet Approved
PindololPindolol may decrease the bronchodilatory activities of Doxofylline.Approved, Investigational
PipequalineThe serum concentration of Doxofylline can be decreased when it is combined with Pipequaline.Experimental
PirbuterolThe risk or severity of adverse effects can be increased when Doxofylline is combined with Pirbuterol.Approved
PiretanideDoxofylline may increase the hypokalemic activities of Piretanide.Approved
PirlindoleThe risk or severity of adverse effects can be increased when Pirlindole is combined with Doxofylline.Approved
PivhydrazineThe risk or severity of adverse effects can be increased when Pivhydrazine is combined with Doxofylline.Withdrawn
PizotifenPizotifen may decrease the vasoconstricting activities of Doxofylline.Approved
PolythiazideDoxofylline may increase the hypokalemic activities of Polythiazide.Approved
PrazosinPrazosin may decrease the vasoconstricting activities of Doxofylline.Approved
PregabalinThe serum concentration of Doxofylline can be decreased when it is combined with Pregabalin.Approved, Illicit, Investigational
PrenalterolThe risk or severity of adverse effects can be increased when Prenalterol is combined with Doxofylline.Experimental
PrimidoneThe serum concentration of Doxofylline can be decreased when it is combined with Primidone.Approved, Vet Approved
ProcaineThe risk or severity of adverse effects can be increased when Procaine is combined with Doxofylline.Approved, Investigational, Vet Approved
ProcarbazineThe risk or severity of adverse effects can be increased when Procarbazine is combined with Doxofylline.Approved, Investigational
ProcaterolThe risk or severity of adverse effects can be increased when Doxofylline is combined with Procaterol.Approved, Investigational
ProgabideThe serum concentration of Doxofylline can be decreased when it is combined with Progabide.Approved, Investigational
PromazinePromazine may decrease the vasoconstricting activities of Doxofylline.Approved, Vet Approved
PropericiazinePropericiazine may decrease the vasoconstricting activities of Doxofylline.Approved, Investigational
PropiomazinePropiomazine may decrease the vasoconstricting activities of Doxofylline.Approved
PropiverinePropiverine may decrease the vasoconstricting activities of Doxofylline.Approved, Investigational
PropranololThe serum concentration of Doxofylline can be increased when it is combined with Propranolol.Approved, Investigational
ProtokylolThe risk or severity of adverse effects can be increased when Doxofylline is combined with Protokylol.Approved, Vet Approved
ProtriptylineThe risk or severity of adverse effects can be increased when Protriptyline is combined with Doxofylline.Approved
PseudoephedrineThe risk or severity of adverse effects can be increased when Pseudoephedrine is combined with Doxofylline.Approved
QuetiapineQuetiapine may decrease the vasoconstricting activities of Doxofylline.Approved
QuinethazoneDoxofylline may increase the hypokalemic activities of Quinethazone.Approved
QuinidineQuinidine may decrease the vasoconstricting activities of Doxofylline.Approved, Investigational
RacepinephrineThe risk or severity of adverse effects can be increased when Doxofylline is combined with Racepinephrine.Approved
RanitidineThe serum concentration of Doxofylline can be increased when it is combined with Ranitidine.Approved
RasagilineThe risk or severity of adverse effects can be increased when Rasagiline is combined with Doxofylline.Approved
RemacemideThe serum concentration of Doxofylline can be decreased when it is combined with Remacemide.Investigational
RiluzoleThe serum concentration of Doxofylline can be decreased when it is combined with Riluzole.Approved, Investigational
RiociguatDoxofylline may increase the hypotensive activities of Riociguat.Approved
RisperidoneRisperidone may decrease the vasoconstricting activities of Doxofylline.Approved, Investigational
RitodrineThe risk or severity of adverse effects can be increased when Doxofylline is combined with Ritodrine.Approved, Investigational
RufinamideThe serum concentration of Doxofylline can be decreased when it is combined with Rufinamide.Approved
SafrazineThe risk or severity of adverse effects can be increased when Safrazine is combined with Doxofylline.Withdrawn
SalbutamolThe risk or severity of adverse effects can be increased when Doxofylline is combined with Salbutamol.Approved, Vet Approved
SalmeterolThe risk or severity of adverse effects can be increased when Doxofylline is combined with Salmeterol.Approved
SelegilineThe risk or severity of adverse effects can be increased when Selegiline is combined with Doxofylline.Approved, Investigational, Vet Approved
SilodosinSilodosin may decrease the vasoconstricting activities of Doxofylline.Approved
SotalolSotalol may decrease the bronchodilatory activities of Doxofylline.Approved
SpironolactoneSpironolactone may decrease the vasoconstricting activities of Doxofylline.Approved
StiripentolThe serum concentration of Doxofylline can be decreased when it is combined with Stiripentol.Approved
SulthiameThe serum concentration of Doxofylline can be decreased when it is combined with Sulthiame.Experimental
SynephrineThe risk or severity of adverse effects can be increased when Synephrine is combined with Doxofylline.Experimental
TamsulosinTamsulosin may decrease the vasoconstricting activities of Doxofylline.Approved, Investigational
TerazosinTerazosin may decrease the vasoconstricting activities of Doxofylline.Approved
TerbutalineThe risk or severity of adverse effects can be increased when Doxofylline is combined with Terbutaline.Approved
TertatololTertatolol may decrease the bronchodilatory activities of Doxofylline.Experimental
TetryzolineThe risk or severity of adverse effects can be increased when Tetryzoline is combined with Doxofylline.Approved
TheophyllineThe risk or severity of adverse effects can be increased when Theophylline is combined with Doxofylline.Approved
ThiopentalThe serum concentration of Doxofylline can be decreased when it is combined with Thiopental.Approved, Vet Approved
ThioproperazineThioproperazine may decrease the vasoconstricting activities of Doxofylline.Approved
ThioridazineThioridazine may decrease the vasoconstricting activities of Doxofylline.Approved, Withdrawn
TiagabineThe serum concentration of Doxofylline can be decreased when it is combined with Tiagabine.Approved, Investigational
TianeptineThe risk or severity of adverse effects can be increased when Tianeptine is combined with Doxofylline.Approved, Investigational
TiletamineThe serum concentration of Doxofylline can be decreased when it is combined with Tiletamine.Vet Approved
TimololTimolol may decrease the bronchodilatory activities of Doxofylline.Approved
TizanidineThe serum concentration of Doxofylline can be decreased when it is combined with Tizanidine.Approved, Investigational
TolazolineTolazoline may decrease the vasoconstricting activities of Doxofylline.Approved, Vet Approved
ToloxatoneThe risk or severity of adverse effects can be increased when Toloxatone is combined with Doxofylline.Approved
TopiramateThe serum concentration of Doxofylline can be decreased when it is combined with Topiramate.Approved
TorasemideDoxofylline may increase the hypokalemic activities of Torasemide.Approved
TramazolineThe risk or severity of adverse effects can be increased when Tramazoline is combined with Doxofylline.Investigational
TramiprosateThe serum concentration of Doxofylline can be decreased when it is combined with Tramiprosate.Investigational
TranylcypromineThe risk or severity of adverse effects can be increased when Tranylcypromine is combined with Doxofylline.Approved, Investigational
TrazodoneTrazodone may decrease the vasoconstricting activities of Doxofylline.Approved, Investigational
TretoquinolThe risk or severity of adverse effects can be increased when Tretoquinol is combined with Doxofylline.Experimental
TrichlormethiazideDoxofylline may increase the hypokalemic activities of Trichlormethiazide.Approved, Vet Approved
TrifluoperazineTrifluoperazine may decrease the vasoconstricting activities of Doxofylline.Approved, Investigational
TrimazosinTrimazosin may decrease the vasoconstricting activities of Doxofylline.Experimental
TrimethadioneThe serum concentration of Doxofylline can be decreased when it is combined with Trimethadione.Approved
TrimipramineThe risk or severity of adverse effects can be increased when Trimipramine is combined with Doxofylline.Approved
TyramineThe risk or severity of adverse effects can be increased when Tyramine is combined with Doxofylline.Investigational, Nutraceutical
UrapidilUrapidil may decrease the vasoconstricting activities of Doxofylline.Investigational
Valproic AcidThe serum concentration of Doxofylline can be decreased when it is combined with Valproic Acid.Approved, Investigational
ValpromideThe serum concentration of Doxofylline can be decreased when it is combined with Valpromide.Experimental
VemurafenibThe risk or severity of QTc prolongation can be increased when Vemurafenib is combined with Doxofylline.Approved
VenlafaxineVenlafaxine may increase the tachycardic activities of Doxofylline.Approved
VerapamilVerapamil may decrease the vasoconstricting activities of Doxofylline.Approved
VigabatrinThe serum concentration of Doxofylline can be decreased when it is combined with Vigabatrin.Approved
VilanterolThe risk or severity of adverse effects can be increased when Doxofylline is combined with Vilanterol.Approved
VinpocetineThe serum concentration of Doxofylline can be decreased when it is combined with Vinpocetine.Investigational
ZaleplonThe serum concentration of Doxofylline can be decreased when it is combined with Zaleplon.Approved, Illicit, Investigational
ZiprasidoneZiprasidone may decrease the vasoconstricting activities of Doxofylline.Approved
ZonisamideThe serum concentration of Doxofylline can be decreased when it is combined with Zonisamide.Approved, Investigational
ZuclopenthixolZuclopenthixol may decrease the vasoconstricting activities of Doxofylline.Approved, Investigational
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
R03DA20 — Combinations of xanthinesR03DA11 — Doxofylline
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]

Drug created on October 28, 2015 14:04 / Updated on July 02, 2018 19:14