Oxtriphylline 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

Similar Structures

Synonyms

Choline theophyllinate
Choline theophylline
Oxtriphylline
Theocolin

Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
Apo Oxtriphylline Tab 100mg	Tablet	100 mg	Oral	Apotex Corporation	1982-12-31	Not applicable
Apo Oxtriphylline Tab 200mg	Tablet	200 mg	Oral	Apotex Corporation	1982-12-31	Not applicable
Apo Oxtriphylline Tab 300mg	Tablet	300 mg	Oral	Apotex Corporation	1982-12-31	Not applicable
Choledyl Elixir 100mg/5ml	Elixir	100 mg	Oral	Erfa Canada 2012 Inc	1976-12-31	Not applicable
Choledyl Pediatric Syr 50mg/5ml	Syrup	50 mg	Oral	Parke Davis Division, Warner Lambert Canada Inc.	1981-12-31	1999-08-13
Choledyl Sa Tablets 400mg	Tablet, extended release	400 mg	Oral	Erfa Canada 2012 Inc	1983-12-31	2005-07-13
Choledyl Sa Tablets 600mg	Tablet, extended release	600 mg	Oral	Erfa Canada 2012 Inc	1982-12-31	2005-07-13
Choledyl Tab 200mg	Tablet	200 mg	Oral	Parke Davis Division, Warner Lambert Canada Inc.	1951-12-31	1999-04-08
Oxtriphylline Tab 200mg	Tablet	200 mg	Oral	Pro Doc Limitee	1983-12-31	1999-08-12
Oxtriphylline Tab 300mg	Tablet	300 mg	Oral	Pro Doc Limitee	1983-12-31	1999-08-12

Generic Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
Novo-triphyl Tab 100mg	Tablet	100 mg	Oral	Novopharm Limited	1981-12-31	2005-08-10
Novo-triphyl Tab 200mg	Tablet	200 mg	Oral	Novopharm Limited	1981-12-31	2005-08-10
Novo-triphyl Tab 300mg	Tablet	300 mg	Oral	Novopharm Limited	1983-12-31	2005-08-10

Mixture Products

Name	Ingredients	Dosage	Route	Labeller	Marketing Start	Marketing End
Choledyl Expectorant Elixir	Oxtriphylline (100 mg) + Guaifenesin (50 mg)	Elixir	Oral	Erfa Canada 2012 Inc	1981-12-31	Not applicable
PMS-oxtriphylline Elixir	Oxtriphylline (20 mg) + Ethanol (.2 ml)	Elixir	Oral	Pharmascience Inc	1992-12-31	2016-10-28

International/Other Brands

Choledyl (Warner Chilcott) / Theocolin (Sannova)

Categories

UNII

3K045XR58X

CAS number

4499-40-5

Weight

Average: 283.3268
Monoisotopic: 283.164439563

Chemical Formula

C₁₂H₂₁N₅O₃

InChI Key

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

Pharmacology

Indication

Used to treat the symptoms of asthma, bronchitis, COPD, and emphysema.

Associated Conditions

Bronchoconstriction

Pharmacodynamics

Oxtriphylline 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 action

Oxtriphylline 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.

Target	Actions	Organism
AcGMP-inhibited 3',5'-cyclic phosphodiesterase A	inhibitor	Humans
AcAMP-specific 3',5'-cyclic phosphodiesterase 4A	inhibitor	Humans
AAdenosine receptor A2a	antagonist	Humans
AAdenosine receptor A1	antagonist	Humans
AHistone deacetylase 2	activator	Humans

Absorption

After 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 binding

With 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 elimination

The kidneys are the main route of elimination for both theophylline and its metabolites, but some unchanged theophylline is eliminated in the feces.

Half life

The 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.

Toxicity

Symptoms 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

Pathways

Not Available

Pharmacogenomic Effects/ADRs

Not Available

Interactions

Drug Interactions

Drug	Interaction
(R)-warfarin	The metabolism of (R)-warfarin can be decreased when combined with Oxtriphylline.
2,5-Dimethoxy-4-ethylamphetamine	The risk or severity of adverse effects can be increased when 2,5-Dimethoxy-4-ethylamphetamine is combined with Oxtriphylline.
2,5-Dimethoxy-4-ethylthioamphetamine	The risk or severity of adverse effects can be increased when 2,5-Dimethoxy-4-ethylthioamphetamine is combined with Oxtriphylline.
3,5-diiodothyropropionic acid	The serum concentration of Oxtriphylline can be increased when it is combined with 3,5-diiodothyropropionic acid.
4-Bromo-2,5-dimethoxyamphetamine	The risk or severity of adverse effects can be increased when 4-Bromo-2,5-dimethoxyamphetamine is combined with Oxtriphylline.
6-Deoxyerythronolide B	The metabolism of Oxtriphylline can be decreased when combined with 6-Deoxyerythronolide B.
6-O-benzylguanine	The metabolism of 6-O-benzylguanine can be decreased when combined with Oxtriphylline.
7-Nitroindazole	7-Nitroindazole may increase the excretion rate of Oxtriphylline which could result in a lower serum level and potentially a reduction in efficacy.
8-azaguanine	The metabolism of 8-azaguanine can be decreased when combined with Oxtriphylline.
8-chlorotheophylline	The metabolism of 8-chlorotheophylline can be decreased when combined with Oxtriphylline.

Food Interactions

Avoid high doses of caffeine.
Take with food to reduce irritation.

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 References

Not Available

External Links

Human Metabolome Database: HMDB0015415
KEGG Drug: D02017
PubChem Compound: 656652
PubChem Substance: 46507376
ChemSpider: 25044543
ChEMBL: CHEMBL1200434
Therapeutic Targets Database: DAP000868
PharmGKB: PA164748137
Drugs.com: Drugs.com Drug Page
Wikipedia: Oxtriphylline

ATC Codes

R03DA20 — Combinations of xanthines

R03DB02 — Choline theophyllinate and adrenergics

R03DA02 — Choline theophyllinate

AHFS Codes

86:16.00 — Respiratory Smooth Muscle Relaxants

Clinical Trials

Clinical Trials: Not Available

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Warner Chilcott Co. Inc.

Dosage forms

Form	Route	Strength
Elixir	Oral	100 mg
Elixir	Oral
Syrup	Oral	50 mg
Tablet, extended release	Oral	400 mg
Tablet, extended release	Oral	600 mg
Tablet	Oral	300 mg
Syrup	Oral	10 mg
Tablet	Oral	100 mg
Tablet	Oral	200 mg

Prices

Unit description	Cost	Unit
Choledyl 20 mg/ml Elixir	0.04USD	ml
Pms-Oxtriphylline 20 mg/ml Elixir	0.02USD	ml

DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.

Patents

Not Available

Properties

State

Solid

Experimental Properties

Property	Value	Source
water solubility	Soluble in alcohol and water.	From Lexicomp.

Predicted Properties

Property	Value	Source
Water Solubility	3.84 mg/mL	ALOGPS
logP	-0.99	ALOGPS
logP	-0.77	ChemAxon
logS	-1.9	ALOGPS
pKa (Strongest Acidic)	7.82	ChemAxon
pKa (Strongest Basic)	-0.78	ChemAxon
Physiological Charge	0	ChemAxon
Hydrogen Acceptor Count	4	ChemAxon
Hydrogen Donor Count	0	ChemAxon
Polar Surface Area	66.4 Å²	ChemAxon
Rotatable Bond Count	2	ChemAxon
Refractivity	45.51 m³·mol^-1	ChemAxon
Polarizability	16.49 Å³	ChemAxon
Number of Rings	2	ChemAxon
Bioavailability	1	ChemAxon
Rule of Five	Yes	ChemAxon
Ghose Filter	No	ChemAxon
Veber's Rule	No	ChemAxon
MDDR-like Rule	No	ChemAxon

Predicted ADMET features

Property	Value	Probability
Human Intestinal Absorption	+	0.585
Blood Brain Barrier	+	0.7679
Caco-2 permeable	-	0.5861
P-glycoprotein substrate	Substrate	0.718
P-glycoprotein inhibitor I	Non-inhibitor	0.9763
P-glycoprotein inhibitor II	Non-inhibitor	0.9261
Renal organic cation transporter	Non-inhibitor	0.8496
CYP450 2C9 substrate	Non-substrate	0.7126
CYP450 2D6 substrate	Non-substrate	0.8089
CYP450 3A4 substrate	Substrate	0.5699
CYP450 1A2 substrate	Non-inhibitor	0.7873
CYP450 2C9 inhibitor	Non-inhibitor	0.937
CYP450 2D6 inhibitor	Non-inhibitor	0.9259
CYP450 2C19 inhibitor	Non-inhibitor	0.9227
CYP450 3A4 inhibitor	Non-inhibitor	0.9707
CYP450 inhibitory promiscuity	Low CYP Inhibitory Promiscuity	0.9716
Ames test	Non AMES toxic	0.6337
Carcinogenicity	Non-carcinogens	0.8347
Biodegradation	Ready biodegradable	0.9052
Rat acute toxicity	2.5809 LD50, mol/kg	Not applicable
hERG inhibition (predictor I)	Weak inhibitor	0.8706
hERG inhibition (predictor II)	Non-inhibitor	0.8959

ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST): Not Available
Spectra: Not 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 / Cholines / Vinylogous amides / Tetraalkylammonium salts / Imidazoles / Heteroaromatic compounds / Ureas / 1,2-aminoalcohols
show 8 more
Substituents: Xanthine / 6-oxopurine / Purinone / Alkaloid or derivatives / Choline / Pyrimidone / Pyrimidine / Heteroaromatic compound / Tetraalkylammonium salt / Vinylogous amide
show 21 more
Molecular Framework: Not Available
External Descriptors: Not Available

Targets

Details1. cGMP-inhibited 3',5'-cyclic phosphodiesterase A

Kind: Protein
Organism: Humans
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
Uniprot Name: cGMP-inhibited 3',5'-cyclic phosphodiesterase A
Molecular Weight: 124978.06 Da

References

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]
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]
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]

Details2. cAMP-specific 3',5'-cyclic phosphodiesterase 4A

Kind: Protein
Organism: Humans
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
Uniprot Name: cAMP-specific 3',5'-cyclic phosphodiesterase 4A
Molecular Weight: 98142.155 Da

References

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]
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]
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]
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]
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]

Details3. Adenosine receptor A2a

Kind: Protein
Organism: Humans
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
Uniprot Name: Adenosine receptor A2a
Molecular Weight: 44706.925 Da

References

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]
Daly JW, Jacobson KA, Ukena D: Adenosine receptors: development of selective agonists and antagonists. Prog Clin Biol Res. 1987;230:41-63. [PubMed:3588607]

Details4. Adenosine receptor A1

Kind: Protein
Organism: Humans
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
Uniprot Name: Adenosine receptor A1
Molecular Weight: 36511.325 Da

References

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]
Daly JW, Jacobson KA, Ukena D: Adenosine receptors: development of selective agonists and antagonists. Prog Clin Biol Res. 1987;230:41-63. [PubMed:3588607]

Details5. Histone deacetylase 2

Kind: Protein
Organism: Humans
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 impo...
Gene Name: HDAC2
Uniprot ID: Q92769
Uniprot Name: Histone deacetylase 2
Molecular Weight: 55363.855 Da

References

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]
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

Details1. Cytochrome P450 1A2

Kind: Protein
Organism: Humans
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 un...
Gene Name: CYP1A2
Uniprot ID: P05177
Uniprot Name: Cytochrome P450 1A2
Molecular Weight: 58293.76 Da

References

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]
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]
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]
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]
Thorn CF, Aklillu E, Klein TE, Altman RB: PharmGKB summary: very important pharmacogene information for CYP1A2. Pharmacogenet Genomics. 2012 Jan;22(1):73-7. doi: 10.1097/FPC.0b013e32834c6efd. [PubMed:21989077]
Drug Interactions: Cytochrome P450 Drug Interaction Table [Link]

Transporters

Details1. Solute carrier family 22 member 7

Kind: Protein
Organism: Humans
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 sulf...
Gene Name: SLC22A7
Uniprot ID: Q9Y694
Uniprot Name: Solute carrier family 22 member 7
Molecular Weight: 60025.025 Da

References

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]

Drug created on June 30, 2007 08:28 / Updated on April 22, 2019 17:13

Oxtriphylline

Identification

Structure for Oxtriphylline (DB01303)

Pharmacology

Interactions

References

Clinical Trials

Pharmacoeconomics

Properties

Spectra

Taxonomy

Targets

References

References

References

References

References

Enzymes

References

Transporters

References