Identification

Name
Dipivefrin
Accession Number
DB00449  (APRD00930)
Type
Small Molecule
Groups
Approved
Description

Dipivefrin is a prodrug of adrenaline, which is used to treat glaucoma. It is available as ophthalmic solution (eye drops).

Structure
Thumb
Synonyms
  • (+-)-4-[1-Hydroxy-2-(methylamino)ethyl]-O-phenylene divavalate
  • 1-(3',4'-Dipivaloyloxyphenyl)-2-methylamino-1-ethanol
  • 4-[1-Hydroxy-2-(methylamino)ethyl]-O-phenylene divavalate
  • Dipivalyl Epinephrine
  • Dipivefrin
  • Dipivefrina
  • Dipivéfrine
  • Dipivefrinum
  • Pro-Epinephrine
External IDs
DPE / K 30081
Product Ingredients
IngredientUNIICASInChI Key
Dipivefrin Hydrochloride5QTH9UHV0K64019-93-8VKFAUCPBMAGVRG-UHFFFAOYSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Dipivefrin HydrochlorideSolution1 mg/1OphthalmicFALCON Pharmaceuticals, Ltd1994-06-30Not applicableUs
Dipivefrin-liq Oph 0.1%Liquid.1 %OphthalmicAlcon, Inc.1995-12-311996-08-16Canada
Dpe Ophthalmic Solution - 0.1%Solution / drops.1 %Ophthalmic; TopicalAlcon, Inc.1995-12-311999-12-23Canada
PropineSolution / drops1 mg/1mLOphthalmicAllergan2001-09-042010-01-04Us
Propine Liq 0.1%Liquid1 mgOphthalmicAllergan1981-12-312011-08-04Canada
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Apo-dipivefrinLiquid0.1 %OphthalmicApotex Corporation2000-07-17Not applicableCanada
Dipivefrin HydrochlorideSolution / drops1 mg/1mLOphthalmicBauch & Lomb Incorporated1995-05-192007-12-01Us
PMS-dipivefrinSolution / drops0.1 %OphthalmicPharmascience Inc1998-08-312016-10-28Canada
Ratio-dipivefrinSolution0.1 %OphthalmicRatiopharm Inc Division Of Teva Canada Limited1995-12-312006-08-04Canada
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
Probeta - Liq OphDipivefrin Hydrochloride (0.1 %) + Levobunolol Hydrochloride (0.5 %)LiquidOphthalmicAllergan1996-08-302012-07-16Canada
International/Other Brands
AKPro (Akorn) / D Epifrin (Allergan) / Diopine (Allergan) / Pivalephrine (Santen Pharmaceutical) / Propine (Allergan) / Thilodrin (Alcon)
Categories
UNII
8Q1PVL543G
CAS number
52365-63-6
Weight
Average: 351.4373
Monoisotopic: 351.204573043
Chemical Formula
C19H29NO5
InChI Key
OCUJLLGVOUDECM-UHFFFAOYSA-N
InChI
InChI=1S/C19H29NO5/c1-18(2,3)16(22)24-14-9-8-12(13(21)11-20-7)10-15(14)25-17(23)19(4,5)6/h8-10,13,20-21H,11H2,1-7H3
IUPAC Name
2-[(2,2-dimethylpropanoyl)oxy]-5-[1-hydroxy-2-(methylamino)ethyl]phenyl 2,2-dimethylpropanoate
SMILES
CNCC(O)C1=CC(OC(=O)C(C)(C)C)=C(OC(=O)C(C)(C)C)C=C1

Pharmacology

Indication

Dipivefrin is a prodrug which is used as initial therapy for the control of intraocular pressure in chronic open-angle glaucoma.

Associated Conditions
Pharmacodynamics

Dipivefrin is a member of a class of drugs known as prodrugs. Prodrugs are usually not active in themselves and require biotransformation to the parent compound before therapeutic activity is seen. These modifications are undertaken to enhance absorption, decrease side effects and enhance stability and comfort, thus making the parent compound a more useful drug. Enhanced absorption makes the prodrug a more efficient delivery system for the parent drug because less drug will be needed to produce the desired therapeutic response. Dipivefrin is a prodrug of epinephrine formed by the diesterification of epinephrine and pivalic acid. The addition of pivaloyl groups to the epinephrine molecule enhances its lipophilic character and, as a consequence, its penetration into the anterior chamber.

Mechanism of action

Dipivefrin is a prodrug with little or no pharmacologically activity until it is hydrolyzed into epinephrine inside the human eye. The liberated epinephrine, an adrenergic agonist, appears to exert its action by stimulating α -and/or β2-adrenergic receptors, leading to a decrease in aqueous production and an enhancement of outflow facility. The dipivefrin prodrug delivery system is a more efficient way of delivering the therapeutic effects of epinephrine, with fewer side effects than are associated with conventional epinephrine therapy.

TargetActionsOrganism
AAlpha-1A adrenergic receptor
agonist
Human
AAlpha-2A adrenergic receptor
agonist
Human
ABeta-2 adrenergic receptor
agonist
Human
ACholinesterase
substrate
Human
UAcetylcholinesterase
inhibitor
Human
Absorption

Well absorbed following occular administration.

Volume of distribution
Not Available
Protein binding
Not Available
Metabolism

Dipivefrin is converted to epinephrine inside the human eye by enzyme hydrolysis.

Route of elimination
Not Available
Half life
Not Available
Clearance
Not Available
Toxicity

Oral LD50 in rat is 183 mg/kg.

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

Interactions

Drug Interactions
DrugInteraction
AbediterolThe risk or severity of adverse effects can be increased when Abediterol is combined with Dipivefrin.
AcebutololAcebutolol may decrease the bronchodilatory activities of Dipivefrin.
AlprenololAlprenolol may decrease the bronchodilatory activities of Dipivefrin.
ArbutamineThe risk or severity of adverse effects can be increased when Arbutamine is combined with Dipivefrin.
ArformoterolThe risk or severity of adverse effects can be increased when Arformoterol is combined with Dipivefrin.
AtenololAtenolol may decrease the bronchodilatory activities of Dipivefrin.
AtomoxetineAtomoxetine may increase the tachycardic activities of Dipivefrin.
AtosibanThe risk or severity of adverse effects can be increased when Dipivefrin is combined with Atosiban.
AzosemideThe risk or severity of hyperkalemia can be increased when Dipivefrin is combined with Azosemide.
BambuterolThe risk or severity of adverse effects can be increased when Bambuterol is combined with Dipivefrin.
Food Interactions
Not Available

References

Synthesis Reference

Hussain, A. and Truelove, J.E.; U.S. Patents 3,809.714; May 7,1974; and 3,839,584; October 1, 1974; both assigned to Inter Rx Research Corp. Henschler, D., Wagner, J. and Hampel, H.; US. Patent 4,085,270; April 18,1978; assigned to Chemisch-Pharmazeutische Fabrik Adolf Klinge & Co. (W. Germany).

General References
Not Available
External Links
Human Metabolome Database
HMDB0014592
KEGG Drug
D02349
KEGG Compound
C06963
PubChem Compound
3105
PubChem Substance
46504716
ChemSpider
2994
ChEBI
4646
ChEMBL
CHEMBL1201262
Therapeutic Targets Database
DAP000593
PharmGKB
PA449364
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
PDRhealth
PDRhealth Drug Page
Wikipedia
Dipivefrin
ATC Codes
S01EA02 — Dipivefrine
AHFS Codes
  • 52:24.00 — Mydriatics
FDA label
Download (60.3 KB)
MSDS
Download (50.2 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4RecruitingTreatmentLabour Pain / Obesity, Morbid1

Pharmacoeconomics

Manufacturers
  • Akorn inc
  • Bausch and lomb pharmaceuticals inc
  • Falcon pharmaceuticals ltd
  • Allergan pharmaceutical
Packagers
  • Allergan Inc.
  • Dispensing Solutions
  • Pacific Pharma Lp
  • Pharmedix
  • Physicians Total Care Inc.
  • Taylor Pharmaceuticals
Dosage forms
FormRouteStrength
LiquidOphthalmic0.1 %
SolutionOphthalmic1 mg/1
Solution / dropsOphthalmic1 mg/1mL
LiquidOphthalmic.1 %
Solution / dropsOphthalmic; Topical.1 %
Solution / dropsOphthalmic0.1 %
LiquidOphthalmic
LiquidOphthalmic1 mg
SolutionOphthalmic0.1 %
Prices
Unit descriptionCostUnit
Propine 0.1% eye drops5.02USD ml
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)146-147Hussain, A. and Truelove, J.E.; U.S. Patents 3,809.714; May 7,1974; and 3,839,584; October 1, 1974; both assigned to Inter Rx Research Corp. Henschler, D., Wagner, J. and Hampel, H.; US. Patent 4,085,270; April 18,1978; assigned to Chemisch-Pharmazeutische Fabrik Adolf Klinge & Co. (W. Germany).
water solubilityFreely soluble as HCl saltNot Available
logP1.7Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0582 mg/mLALOGPS
logP3.17ALOGPS
logP3.71ChemAxon
logS-3.8ALOGPS
pKa (Strongest Acidic)14ChemAxon
pKa (Strongest Basic)9.33ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area84.86 Å2ChemAxon
Rotatable Bond Count9ChemAxon
Refractivity94.94 m3·mol-1ChemAxon
Polarizability38.65 Å3ChemAxon
Number of Rings1ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.8575
Blood Brain Barrier-0.9747
Caco-2 permeable-0.7458
P-glycoprotein substrateSubstrate0.7499
P-glycoprotein inhibitor INon-inhibitor0.6617
P-glycoprotein inhibitor IINon-inhibitor0.7348
Renal organic cation transporterNon-inhibitor0.9396
CYP450 2C9 substrateNon-substrate0.8238
CYP450 2D6 substrateNon-substrate0.8369
CYP450 3A4 substrateNon-substrate0.5056
CYP450 1A2 substrateNon-inhibitor0.9046
CYP450 2C9 inhibitorNon-inhibitor0.9071
CYP450 2D6 inhibitorNon-inhibitor0.9231
CYP450 2C19 inhibitorNon-inhibitor0.9129
CYP450 3A4 inhibitorNon-inhibitor0.5546
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9757
Ames testNon AMES toxic0.9063
CarcinogenicityNon-carcinogens0.8624
BiodegradationNot ready biodegradable0.7095
Rat acute toxicity2.2818 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9635
hERG inhibition (predictor II)Non-inhibitor0.8847
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
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 phenol esters. These are aromatic compounds containing a benzene ring substituted by a hydroxyl group and an ester group.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Phenol esters
Sub Class
Not Available
Direct Parent
Phenol esters
Alternative Parents
Phenoxy compounds / Aralkylamines / Dicarboxylic acids and derivatives / Secondary alcohols / Carboxylic acid esters / Amino acids and derivatives / 1,2-aminoalcohols / Dialkylamines / Organopnictogen compounds / Organic oxides
show 3 more
Substituents
Phenol ester / Phenoxy compound / Aralkylamine / Monocyclic benzene moiety / Dicarboxylic acid or derivatives / 1,2-aminoalcohol / Amino acid or derivatives / Carboxylic acid ester / Secondary alcohol / Carboxylic acid derivative
show 14 more
Molecular Framework
Aromatic homomonocyclic compounds
External Descriptors
ethanolamines, pivalate ester (CHEBI:4646)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Agonist
General Function
Protein heterodimerization activity
Specific Function
This alpha-adrenergic receptor mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system. Its effect is mediated by G(q) and G(11) prot...
Gene Name
ADRA1A
Uniprot ID
P35348
Uniprot Name
Alpha-1A adrenergic receptor
Molecular Weight
51486.005 Da
References
  1. Sanbe A, Tanaka Y, Fujiwara Y, Tsumura H, Yamauchi J, Cotecchia S, Koike K, Tsujimoto G, Tanoue A: Alpha1-adrenoceptors are required for normal male sexual function. Br J Pharmacol. 2007 Oct;152(3):332-40. Epub 2007 Jul 2. [PubMed:17603545]
  2. Tomiyama Y, Kobayashi K, Tadachi M, Kobayashi S, Inada Y, Kobayashi M, Yamazaki Y: Expressions and mechanical functions of alpha1-adrenoceptor subtypes in hamster ureter. Eur J Pharmacol. 2007 Nov 14;573(1-3):201-5. Epub 2007 Jul 6. [PubMed:17658513]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Agonist
General Function
Thioesterase binding
Specific Function
Alpha-2 adrenergic receptors mediate the catecholamine-induced inhibition of adenylate cyclase through the action of G proteins. The rank order of potency for agonists of this receptor is oxymetazo...
Gene Name
ADRA2A
Uniprot ID
P08913
Uniprot Name
Alpha-2A adrenergic receptor
Molecular Weight
48956.275 Da
References
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [PubMed:17139284]
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [PubMed:17016423]
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. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]
  2. Ozakca I, Arioglu E, Guner S, Altan VM, Ozcelikay AT: Role of beta-3-adrenoceptor in catecholamine-induced relaxations in gastric fundus from control and diabetic rats. Pharmacology. 2007;80(4):227-38. Epub 2007 Jul 6. [PubMed:17622774]
  3. Prenner L, Sieben A, Zeller K, Weiser D, Haberlein H: Reduction of high-affinity beta2-adrenergic receptor binding by hyperforin and hyperoside on rat C6 glioblastoma cells measured by fluorescence correlation spectroscopy. Biochemistry. 2007 May 1;46(17):5106-13. Epub 2007 Apr 7. [PubMed:17417877]
  4. Lucin KM, Sanders VM, Jones TB, Malarkey WB, Popovich PG: Impaired antibody synthesis after spinal cord injury is level dependent and is due to sympathetic nervous system dysregulation. Exp Neurol. 2007 Sep;207(1):75-84. Epub 2007 Jun 2. [PubMed:17597612]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Substrate
General Function
Identical protein binding
Specific Function
Esterase with broad substrate specificity. Contributes to the inactivation of the neurotransmitter acetylcholine. Can degrade neurotoxic organophosphate esters.
Gene Name
BCHE
Uniprot ID
P06276
Uniprot Name
Cholinesterase
Molecular Weight
68417.575 Da
References
  1. Nakamura M, Shirasawa E, Hikida M: Characterization of esterases involved in the hydrolysis of dipivefrin hydrochloride. Ophthalmic Res. 1993;25(1):46-51. [PubMed:8446367]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Serine hydrolase activity
Specific Function
Terminates signal transduction at the neuromuscular junction by rapid hydrolysis of the acetylcholine released into the synaptic cleft. Role in neuronal apoptosis.
Gene Name
ACHE
Uniprot ID
P22303
Uniprot Name
Acetylcholinesterase
Molecular Weight
67795.525 Da
References
  1. Nakamura M, Shirasawa E, Hikida M: Characterization of esterases involved in the hydrolysis of dipivefrin hydrochloride. Ophthalmic Res. 1993;25(1):46-51. [PubMed:8446367]

Drug created on June 13, 2005 07:24 / Updated on October 16, 2018 08:26