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Identification
NameOxtriphylline
Accession NumberDB01303
TypeSmall Molecule
GroupsApproved
DescriptionOxtriphylline is the choline salt form of theophylline. Once in the body, theophylline is released and acts as a phosphodiesterase inhibitor, adenosine receptor blocker, and histone deacetylase activator. Its main physiological reponse is to dilate the bronchioles. As such, oxytriphylline is indicated mainly for asthma, bronchospasm, and COPD (i.e. all the same indications as the other theophyllines). It is marketed under the name Choledyl SA, and several forms of oxytriphylline have been discontinued. In the US, oxtriphylline is no longer available.
Structure
Thumb
Synonyms
Choline theophyllinate
Choline theophylline
Oxtriphylline
Theocolin
Theophyline - choline mixt
External Identifiers Not Available
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Choledyl Elixir 100mg/5mlelixir100 mgoralErfa Canada 2012 Inc1976-12-31Not applicableCanada
Choledyl Pediatric Syr 50mg/5mlsyrup50 mgoralParke Davis Division, Warner Lambert Canada Inc.1981-12-311999-08-13Canada
Choledyl Sa Tablets 400mgtablet (extended-release)400 mgoralErfa Canada 2012 Inc1983-12-312005-07-13Canada
Choledyl Sa Tablets 600mgtablet (extended-release)600 mgoralErfa Canada 2012 Inc1982-12-312005-07-13Canada
Choledyl Tab 200mgtablet200 mgoralParke Davis Division, Warner Lambert Canada Inc.1951-12-311999-04-08Canada
Novo-triphyl Tab 100mgtablet100 mgoralNovopharm Limited1981-12-312005-08-10Canada
Novo-triphyl Tab 200mgtablet200 mgoralNovopharm Limited1981-12-312005-08-10Canada
Novo-triphyl Tab 300mgtablet300 mgoralNovopharm Limited1983-12-312005-08-10Canada
Oxtriphylline Tab 200mgtablet200 mgoralPro Doc Limitee1983-12-311999-08-12Canada
Oxtriphylline Tab 300mgtablet300 mgoralPro Doc Limitee1983-12-311999-08-12Canada
PMS Oxtriphylline Syr Pediatric 10mg/mlsyrup10 mgoralPharmascience Inc1996-12-31Not applicableCanada
Rouphylline Syr 10mg/mlsyrup10 mgoralRougier Pharma Division Of Ratiopharm Inc1975-12-312001-09-05Canada
Rouphylline Tab 100mgtablet100 mgoralRougier Pharma Division Of Ratiopharm Inc1980-12-311999-09-27Canada
Rouphylline Tab 200mgtablet200 mgoralRougier Pharma Division Of Ratiopharm Inc1980-12-311999-09-27Canada
Approved Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Apo Oxtriphylline Tab 100mgtablet100 mgoralApotex Inc1982-12-31Not applicableCanada
Apo Oxtriphylline Tab 200mgtablet200 mgoralApotex Inc1982-12-31Not applicableCanada
Apo Oxtriphylline Tab 300mgtablet300 mgoralApotex Inc1982-12-31Not applicableCanada
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International Brands
NameCompany
CholedylWarner Chilcott
TheocolinSannova
Brand mixtures
NameLabellerIngredients
Choledyl Expectorant ElixirErfa Canada 2012 Inc
PMS-oxtriphylline ElixirPharmascience Inc
SaltsNot Available
Categories
UNII3K045XR58X
CAS number4499-40-5
WeightAverage: 283.3268
Monoisotopic: 283.164439563
Chemical FormulaC12H21N5O3
InChI KeyInChIKey=RLANKEDHRWMNRO-UHFFFAOYSA-M
InChI
InChI=1S/C7H8N4O2.C5H14NO/c1-10-5-4(8-3-9-5)6(12)11(2)7(10)13;1-6(2,3)4-5-7/h3H,1-2H3,(H,8,9,12);7H,4-5H2,1-3H3/q;+1/p-1
IUPAC Name
(2-hydroxyethyl)trimethylazanium; 1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-7-ide
SMILES
C[N+](C)(C)CCO.CN1C2=C([N-]C=N2)C(=O)N(C)C1=O
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as alkaloids and derivatives. These are naturally occurring chemical compounds that contain mostly basic nitrogen atoms. This group also includes some related compounds with neutral and even weakly acidic properties. Also some synthetic compounds of similar structure are attributed to alkaloids. In addition to carbon, hydrogen and nitrogen, alkaloids may also contain oxygen, sulfur and more rarely other elements such as chlorine, bromine, and phosphorus.
KingdomOrganic compounds
Super ClassAlkaloids and derivatives
ClassNot Available
Sub ClassNot Available
Direct ParentAlkaloids and derivatives
Alternative Parents
Substituents
  • Alkaloid or derivatives
  • Xanthine
  • Purinone
  • 6-oxopurine
  • Purine
  • Imidazopyrimidine
  • Pyrimidone
  • Choline
  • Pyrimidine
  • Heteroaromatic compound
  • Vinylogous amide
  • Quaternary ammonium salt
  • Imidazole
  • Azole
  • Urea
  • Lactam
  • 1,2-aminoalcohol
  • Azacycle
  • Organoheterocyclic compound
  • Alkanolamine
  • Hydrocarbon derivative
  • Primary alcohol
  • Organooxygen compound
  • Organonitrogen compound
  • Amine
  • Alcohol
  • Organic zwitterion
  • Aromatic heteropolycyclic compound
  • Aliphatic acyclic compound
Molecular FrameworkNot Available
External DescriptorsNot Available
Pharmacology
IndicationUsed to treat the symptoms of asthma, bronchitis, COPD, and emphysema.
PharmacodynamicsOxtriphylline is a bronchodilator. Oxtriphylline works in several ways: it relaxes muscles in your lungs and chest to allow more air in, decreases the sensitivity of your lungs to allergens and other substances that cause inflammation, and increases the contractions of your diaphragm to draw more air into the lungs.
Mechanism of actionOxtriphylline is a choline salt of theophylline. After ingestion, theophylline is released from oxytriphylline, and theophylline relaxes the smooth muscle of the bronchial airways and pulmonary blood vessels and reduces airway responsiveness to histamine, methacholine, adenosine, and allergen. Theophylline competitively inhibits type III and type IV phosphodiesterase (PDE), the enzyme responsible for breaking down cyclic AMP in smooth muscle cells, possibly resulting in bronchodilation. Theophylline also binds to the adenosine A2B receptor and blocks adenosine mediated bronchoconstriction. In inflammatory states, theophylline activates histone deacetylase to prevent transcription of inflammatory genes that require the acetylation of histones for transcription to begin.
Related Articles
AbsorptionAfter ingestion, theophylline is released from oxytriphylline in the acidic environment of the stomach.
Volume of distribution

Theophylline has an apparent volume of distribution of 0.3–0.7 L/kg in children and adults, and the Vd is about twice that of an adult in premature infants.

Protein bindingWith a serum concentrations of 17 mcg/mL, adults and children have about 56% theophylline bound to plasma protein, and premature infants have about 36%.
Metabolism

Theophylline undergoes hepatic metabolism to 1,3-dimethyluric acid, 1-methyluric acid, and 3-methylxanthine.

Route of eliminationThe kidneys are the main route of elimination for both theophylline and its metabolites, but some unchanged theophylline is eliminated in the feces.
Half lifeThe serum half life varies greatly between patients and in age. The half life range for a healthy, nonsmoking adult is 3-12.8 hours, for children is 1.5–9.5 hours, and for for premature infants is 15–58 hours.
Clearance

Theophylline has an average clearance in children (over 6 months) of 1.45 mL/kg per minute, and in healthy, nonsmoking adults of 0.65 mL/kg per hour.

ToxicitySymptoms of toxicity include abdominal pain (continuing or severe), confusion or change in behavior, convulsions (seizures), dark or bloody vomit, diarrhea, dizziness or lightheadedness, fast and/or irregular heartbeat, nervousness or restlessness (continuing), and trembling (continuing).
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.585
Blood Brain Barrier+0.7679
Caco-2 permeable-0.5861
P-glycoprotein substrateSubstrate0.718
P-glycoprotein inhibitor INon-inhibitor0.9763
P-glycoprotein inhibitor IINon-inhibitor0.9261
Renal organic cation transporterNon-inhibitor0.8496
CYP450 2C9 substrateNon-substrate0.7126
CYP450 2D6 substrateNon-substrate0.8089
CYP450 3A4 substrateSubstrate0.5699
CYP450 1A2 substrateNon-inhibitor0.7873
CYP450 2C9 inhibitorNon-inhibitor0.937
CYP450 2D6 inhibitorNon-inhibitor0.9259
CYP450 2C19 inhibitorNon-inhibitor0.9227
CYP450 3A4 inhibitorNon-inhibitor0.9707
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9716
Ames testNon AMES toxic0.6337
CarcinogenicityNon-carcinogens0.8347
BiodegradationReady biodegradable0.9052
Rat acute toxicity2.5809 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.8706
hERG inhibition (predictor II)Non-inhibitor0.8959
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
ManufacturersNot Available
Packagers
Dosage forms
FormRouteStrength
Tabletoral100 mg
Tabletoral200 mg
Tabletoral300 mg
Elixiroral100 mg
Elixiroral
Syruporal50 mg
Tablet (extended-release)oral400 mg
Tablet (extended-release)oral600 mg
Syruporal10 mg
Prices
Unit descriptionCostUnit
Choledyl 20 mg/ml Elixir0.04USD ml
Pms-Oxtriphylline 20 mg/ml Elixir0.02USD ml
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
PatentsNot Available
Properties
StateSolid
Experimental Properties
PropertyValueSource
water solubilitySoluble in alcohol and water.From Lexicomp.
Predicted Properties
PropertyValueSource
Water Solubility3.84 mg/mLALOGPS
logP-0.99ALOGPS
logP-0.77ChemAxon
logS-1.9ALOGPS
pKa (Strongest Acidic)7.82ChemAxon
pKa (Strongest Basic)-0.78ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area66.4 Å2ChemAxon
Rotatable Bond Count2ChemAxon
Refractivity45.51 m3·mol-1ChemAxon
Polarizability16.49 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
References
Synthesis Reference

Ladenburg, K., Duesel, B.F. and Fand,T.I.; U S . Patent 2,776,287; January 1,1957; assigned
to Nepera Chemical Co., Inc.

General ReferencesNot Available
External Links
ATC CodesR03DB02R03DA02
AHFS Codes
  • 86:16.00
PDB EntriesNot Available
FDA labelNot Available
MSDSNot Available
Interactions
Drug Interactions
Drug
AbirateroneThe serum concentration of Oxtriphylline can be increased when it is combined with Abiraterone.
AzithromycinThe metabolism of Oxtriphylline can be decreased when combined with Azithromycin.
BortezomibThe metabolism of Oxtriphylline can be decreased when combined with Bortezomib.
CaffeineThe metabolism of Oxtriphylline can be decreased when combined with Caffeine.
CarbamazepineThe metabolism of Oxtriphylline can be increased when combined with Carbamazepine.
CitalopramThe metabolism of Oxtriphylline can be decreased when combined with Citalopram.
ClotrimazoleThe metabolism of Oxtriphylline can be decreased when combined with Clotrimazole.
Cyproterone acetateThe serum concentration of Oxtriphylline can be decreased when it is combined with Cyproterone acetate.
DeferasiroxThe serum concentration of Oxtriphylline can be increased when it is combined with Deferasirox.
FluvoxamineThe metabolism of Oxtriphylline can be decreased when combined with Fluvoxamine.
LidocaineThe metabolism of Oxtriphylline can be decreased when combined with Lidocaine.
MexiletineThe metabolism of Oxtriphylline can be decreased when combined with Mexiletine.
NevirapineThe metabolism of Oxtriphylline can be decreased when combined with Nevirapine.
OsimertinibThe serum concentration of Oxtriphylline can be decreased when it is combined with Osimertinib.
Peginterferon alfa-2bThe serum concentration of Oxtriphylline can be increased when it is combined with Peginterferon alfa-2b.
PhenobarbitalThe metabolism of Oxtriphylline can be increased when combined with Phenobarbital.
PrimidoneThe metabolism of Oxtriphylline can be increased when combined with Primidone.
RifampicinThe metabolism of Oxtriphylline can be increased when combined with Rifampicin.
RopiniroleThe metabolism of Oxtriphylline can be decreased when combined with Ropinirole.
SimeprevirThe metabolism of Oxtriphylline can be decreased when combined with Simeprevir.
TenofovirThe metabolism of Oxtriphylline can be decreased when combined with Tenofovir.
TeriflunomideThe serum concentration of Oxtriphylline can be decreased when it is combined with Teriflunomide.
TheophyllineThe metabolism of Oxtriphylline can be decreased when combined with Theophylline.
TiclopidineThe metabolism of Oxtriphylline can be decreased when combined with Ticlopidine.
VemurafenibThe serum concentration of Oxtriphylline can be increased when it is combined with Vemurafenib.
Food Interactions
  • Avoid high doses of caffeine.
  • Take with food to reduce irritation.

Targets

Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
inhibitor
General Function:
Metal ion 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.
Gene Name:
PDE3A
Uniprot ID:
Q14432
Molecular Weight:
124978.06 Da
References
  1. Rickards KJ, Andrews MJ, Waterworth TH, Alexander GB, Cunningham FM: Differential effects of phosphodiesterase inhibitors on platelet activating factor (PAF)- and adenosine diphosphate (ADP)-induced equine platelet aggregation. J Vet Pharmacol Ther. 2003 Aug;26(4):277-82. [PubMed:12887610 ]
  2. Wu BN, Lin RJ, Lo YC, Shen KP, Wang CC, Lin YT, Chen IJ: KMUP-1, a xanthine derivative, induces relaxation of guinea-pig isolated trachea: the role of the epithelium, cyclic nucleotides and K+ channels. Br J Pharmacol. 2004 Aug;142(7):1105-14. Epub 2004 Jul 5. [PubMed:15237094 ]
  3. Kajikawa S, Kigami D, Nakayama H, Doi K: Changes in submaxillary gland gene expression in F344 rats by multiple dosing of theophylline. Exp Anim. 2006 Apr;55(2):143-6. [PubMed:16651698 ]
Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
inhibitor
General Function:
Metal ion binding
Specific Function:
Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes.
Gene Name:
PDE4A
Uniprot ID:
P27815
Molecular Weight:
98142.155 Da
References
  1. Wang K, Chen JQ, Chen Z, Chen JC: Inhibition of human phosphodiesterase 4A expressed in yeast cell GL62 by theophylline, rolipram, and acetamide-45. Acta Pharmacol Sin. 2002 Nov;23(11):1013-7. [PubMed:12421478 ]
  2. Haider S: Cyclic AMP level and phosphodiesterase activity during 17alpha,20beta-dihydroxy-4-pregnen-3-one induction and theophylline inhibition of oocyte maturation in the catfish, Clarias batrachus. Comp Biochem Physiol A Mol Integr Physiol. 2003 Feb;134(2):267-74. [PubMed:12547256 ]
  3. Rickards KJ, Andrews MJ, Waterworth TH, Alexander GB, Cunningham FM: Differential effects of phosphodiesterase inhibitors on platelet activating factor (PAF)- and adenosine diphosphate (ADP)-induced equine platelet aggregation. J Vet Pharmacol Ther. 2003 Aug;26(4):277-82. [PubMed:12887610 ]
  4. Usta C, Sadan G, Tuncel B: The effect of the indomethacin on phosphodiesterase inhibitors mediated responses in isolated trachea preparations. Prostaglandins Leukot Essent Fatty Acids. 2004 Sep;71(3):137-41. [PubMed:15253881 ]
  5. Lee JM, Zemans RL, Hejazi M, Chin BB, Ladenson PW, Caturegli P: Modulation of thyroidal radioiodine uptake by theophylline. Exp Mol Pathol. 2004 Oct;77(2):116-20. [PubMed:15351234 ]
Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
antagonist
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
Molecular Weight:
44706.925 Da
References
  1. Pechlivanova DM, Georgiev VP: Effects of single and long-term theophylline treatment on the threshold of mechanical nociception: contribution of adenosine A1 and alpha2-adrenoceptors. Methods Find Exp Clin Pharmacol. 2005 Nov;27(9):659-64. [PubMed:16357952 ]
  2. Daly JW, Jacobson KA, Ukena D: Adenosine receptors: development of selective agonists and antagonists. Prog Clin Biol Res. 1987;230:41-63. [PubMed:3588607 ]
Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
antagonist
General Function:
Purine nucleoside binding
Specific Function:
Receptor for adenosine. The activity of this receptor is mediated by G proteins which inhibit adenylyl cyclase.
Gene Name:
ADORA1
Uniprot ID:
P30542
Molecular Weight:
36511.325 Da
References
  1. Nantwi KD, Basura GJ, Goshgarian HG: Adenosine A1 receptor mRNA expression and the effects of systemic theophylline administration on respiratory function 4 months after C2 hemisection. J Spinal Cord Med. 2003 Winter;26(4):364-71. [PubMed:14992338 ]
  2. Daly JW, Jacobson KA, Ukena D: Adenosine receptors: development of selective agonists and antagonists. Prog Clin Biol Res. 1987;230:41-63. [PubMed:3588607 ]
Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
activator
General Function:
Transcription factor binding
Specific Function:
Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes. Forms transcriptional repressor c...
Gene Name:
HDAC2
Uniprot ID:
Q92769
Molecular Weight:
55363.855 Da
References
  1. Cosio BG, Tsaprouni L, Ito K, Jazrawi E, Adcock IM, Barnes PJ: Theophylline restores histone deacetylase activity and steroid responses in COPD macrophages. J Exp Med. 2004 Sep 6;200(5):689-95. Epub 2004 Aug 30. [PubMed:15337792 ]
  2. Ito K, Lim S, Caramori G, Cosio B, Chung KF, Adcock IM, Barnes PJ: A molecular mechanism of action of theophylline: Induction of histone deacetylase activity to decrease inflammatory gene expression. Proc Natl Acad Sci U S A. 2002 Jun 25;99(13):8921-6. Epub 2002 Jun 17. [PubMed:12070353 ]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
unknown
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 unrelated compounds, including steroids, fatty acids, and xenobiotics. Most active in catalyzing 2-hydroxylation. Caffeine is metabolized primarily by cytochrome CYP1A2 in the liver through an initial N...
Gene Name:
CYP1A2
Uniprot ID:
P05177
Molecular Weight:
58293.76 Da
References
  1. Brosen K: Drug interactions and the cytochrome P450 system. The role of cytochrome P450 1A2. Clin Pharmacokinet. 1995;29 Suppl 1:20-5. [PubMed:8846619 ]
  2. Wang B, Zhou SF: Synthetic and natural compounds that interact with human cytochrome P450 1A2 and implications in drug development. Curr Med Chem. 2009;16(31):4066-218. [PubMed:19754423 ]
  3. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256 ]
  4. Sarkar MA, Hunt C, Guzelian PS, Karnes HT: Characterization of human liver cytochromes P-450 involved in theophylline metabolism. Drug Metab Dispos. 1992 Jan-Feb;20(1):31-7. [PubMed:1346993 ]
  5. Drug Interactions: Cytochrome P450 Drug Interaction Table [Link]

Transporters

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inhibitor
General Function:
Sodium-independent organic anion transmembrane transporter activity
Specific Function:
Mediates sodium-independent multispecific organic anion transport. Transport of prostaglandin E2, prostaglandin F2, tetracycline, bumetanide, estrone sulfate, glutarate, dehydroepiandrosterone sulfate, allopurinol, 5-fluorouracil, paclitaxel, L-ascorbic acid, salicylate, ethotrexate, and alpha-ketoglutarate.
Gene Name:
SLC22A7
Uniprot ID:
Q9Y694
Molecular Weight:
60025.025 Da
References
  1. Kobayashi Y, Sakai R, Ohshiro N, Ohbayashi M, Kohyama N, Yamamoto T: Possible involvement of organic anion transporter 2 on the interaction of theophylline with erythromycin in the human liver. Drug Metab Dispos. 2005 May;33(5):619-22. Epub 2005 Feb 11. [PubMed:15708966 ]
Comments
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Drug created on June 30, 2007 08:28 / Updated on August 17, 2016 12:23