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Identification
NameDipivefrin
Accession NumberDB00449  (APRD00930)
TypeSmall Molecule
GroupsApproved
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 Identifiers
  • DPE
  • K 30081
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Dipivefrin-liq Oph 0.1%liquid.1 %ophthalmicAlcon Canada Inc1995-12-311996-08-16Canada
Dpe Ophthalmic Solution - 0.1%drops.1 %ophthalmic; topicalAlcon Canada Inc1995-12-311999-12-23Canada
PMS-dipivefrindrops0.1 %ophthalmicPharmascience Inc1998-08-31Not applicableCanada
Propine Liq 0.1%liquid1 mgophthalmicAllergan Inc1981-12-312011-08-04Canada
Ratio-dipivefrinsolution0.1 %ophthalmicRatiopharm Inc Division Of Teva Canada Limited1995-12-312006-08-04Canada
Approved Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Apo-dipivefrinliquid0.1 %ophthalmicApotex Inc2000-07-17Not applicableCanada
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International Brands
NameCompany
AKProAkorn
D EpifrinAllergan
DiopineAllergan
PivalephrineSanten Pharmaceutical
PropineAllergan
ThilodrinAlcon
Brand mixtures
NameLabellerIngredients
Probeta - Liq OphAllergan Inc
Salts
Name/CASStructureProperties
Dipivefrin Hydrochloride
Thumb
  • InChI Key: VKFAUCPBMAGVRG-UHFFFAOYNA-N
  • Monoisotopic Mass: 387.181250782
  • Average Mass: 387.898
DBSALT000626
Categories
UNII8Q1PVL543G
CAS number52365-63-6
WeightAverage: 351.4373
Monoisotopic: 351.204573043
Chemical FormulaC19H29NO5
InChI KeyInChIKey=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
Taxonomy
DescriptionThis 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.
KingdomOrganic compounds
Super ClassBenzenoids
ClassBenzene and substituted derivatives
Sub ClassPhenol esters
Direct ParentPhenol esters
Alternative Parents
Substituents
  • Phenol ester
  • Aralkylamine
  • Dicarboxylic acid or derivatives
  • Secondary alcohol
  • Carboxylic acid ester
  • 1,2-aminoalcohol
  • Secondary amine
  • Secondary aliphatic amine
  • Carboxylic acid derivative
  • Hydrocarbon derivative
  • Aromatic alcohol
  • Organooxygen compound
  • Organonitrogen compound
  • Carbonyl group
  • Amine
  • Alcohol
  • Aromatic homomonocyclic compound
Molecular FrameworkAromatic homomonocyclic compounds
External DescriptorsNot Available
Pharmacology
IndicationDipivefrin is a prodrug which is used as initial therapy for the control of intraocular pressure in chronic open-angle glaucoma.
PharmacodynamicsDipivefrin 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 actionDipivefrin 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.
Related Articles
AbsorptionWell absorbed following occular administration.
Volume of distributionNot Available
Protein bindingNot Available
Metabolism

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

Route of eliminationNot Available
Half lifeNot Available
ClearanceNot Available
ToxicityOral LD50 in rat is 183 mg/kg.
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+0.8575
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 )
Pharmacoeconomics
Manufacturers
  • Akorn inc
  • Bausch and lomb pharmaceuticals inc
  • Falcon pharmaceuticals ltd
  • Allergan pharmaceutical
Packagers
Dosage forms
FormRouteStrength
Liquidophthalmic0.1 %
Liquidophthalmic.1 %
Dropsophthalmic; topical.1 %
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.
PatentsNot Available
Properties
StateSolid
Experimental Properties
PropertyValueSource
melting point146-147Hussain, 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 RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
Spectra
Spectrum TypeDescriptionSplash Key
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, NegativeNot 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 ReferencesNot Available
External Links
ATC CodesS01EA02
AHFS Codes
  • 52:24.00
PDB EntriesNot Available
FDA labelDownload (60.3 KB)
MSDSDownload (50.2 KB)
Interactions
Drug Interactions
Drug
AcebutololThe risk or severity of adverse effects can be increased when Acebutolol is combined with Dipivefrin.
AlfuzosinAlfuzosin may decrease the vasoconstricting activities of Dipivefrin.
AmitriptylineThe therapeutic efficacy of Dipivefrin can be decreased when used in combination with Amitriptyline.
AmoxapineThe therapeutic efficacy of Dipivefrin can be decreased when used in combination with Amoxapine.
AmphetamineThe risk or severity of adverse effects can be increased when Amphetamine is combined with Dipivefrin.
AtenololDipivefrin may increase the atrioventricular blocking (AV block) activities of Atenolol.
AtomoxetineAtomoxetine may increase the hypertensive activities of Dipivefrin.
BendroflumethiazideDipivefrin may increase the atrioventricular blocking (AV block) activities of Bendroflumethiazide.
BenzphetamineThe risk or severity of adverse effects can be increased when Benzphetamine is combined with Dipivefrin.
BetaxololDipivefrin may increase the atrioventricular blocking (AV block) activities of Betaxolol.
BisoprololDipivefrin may increase the atrioventricular blocking (AV block) activities of Bisoprolol.
BromocriptineBromocriptine may increase the hypertensive activities of Dipivefrin.
CabergolineCabergoline may increase the hypertensive activities of Dipivefrin.
CarteololDipivefrin may increase the atrioventricular blocking (AV block) activities of Carteolol.
CarvedilolDipivefrin may increase the atrioventricular blocking (AV block) activities of Carvedilol.
ChlorphentermineThe risk or severity of adverse effects can be increased when Chlorphentermine is combined with Dipivefrin.
ClenbuterolThe risk or severity of adverse effects can be increased when Clenbuterol is combined with Dipivefrin.
ClomipramineThe therapeutic efficacy of Dipivefrin can be decreased when used in combination with Clomipramine.
DesipramineThe therapeutic efficacy of Dipivefrin can be decreased when used in combination with Desipramine.
DesvenlafaxineDesvenlafaxine may decrease the antihypertensive activities of Dipivefrin.
DihydroergotamineDihydroergotamine may increase the hypertensive activities of Dipivefrin.
DobutamineThe risk or severity of adverse effects can be increased when Dobutamine is combined with Dipivefrin.
DopamineThe risk or severity of adverse effects can be increased when Dopamine is combined with Dipivefrin.
DoxazosinDoxazosin may decrease the vasoconstricting activities of Dipivefrin.
DoxepinThe therapeutic efficacy of Dipivefrin can be decreased when used in combination with Doxepin.
DoxofyllineThe risk or severity of adverse effects can be increased when Dipivefrin is combined with Doxofylline.
DronabinolDronabinol may increase the tachycardic activities of Dipivefrin.
DuloxetineDuloxetine may increase the tachycardic activities of Dipivefrin.
EpinephrineThe risk or severity of adverse effects can be increased when Epinephrine is combined with Dipivefrin.
ErgonovineErgonovine may increase the hypertensive activities of Dipivefrin.
ErgotamineErgotamine may increase the hypertensive activities of Dipivefrin.
EsmololDipivefrin may increase the atrioventricular blocking (AV block) activities of Esmolol.
FenoterolThe risk or severity of adverse effects can be increased when Fenoterol is combined with Dipivefrin.
FormoterolThe risk or severity of adverse effects can be increased when Formoterol is combined with Dipivefrin.
ImipramineThe therapeutic efficacy of Dipivefrin can be decreased when used in combination with Imipramine.
IobenguaneThe therapeutic efficacy of Iobenguane can be decreased when used in combination with Dipivefrin.
IsoprenalineThe risk or severity of adverse effects can be increased when Isoprenaline is combined with Dipivefrin.
LabetalolThe risk or severity of adverse effects can be increased when Labetalol is combined with Dipivefrin.
LevomilnacipranLevomilnacipran may decrease the antihypertensive activities of Dipivefrin.
LinezolidLinezolid may increase the hypertensive activities of Dipivefrin.
MephentermineThe risk or severity of adverse effects can be increased when Mephentermine is combined with Dipivefrin.
MetaraminolThe risk or severity of adverse effects can be increased when Metaraminol is combined with Dipivefrin.
MethamphetamineThe risk or severity of adverse effects can be increased when Methamphetamine is combined with Dipivefrin.
MethoxamineThe risk or severity of adverse effects can be increased when Methoxamine is combined with Dipivefrin.
MetoprololDipivefrin may increase the atrioventricular blocking (AV block) activities of Metoprolol.
MidodrineThe risk or severity of adverse effects can be increased when Midodrine is combined with Dipivefrin.
MilnacipranMilnacipran may decrease the antihypertensive activities of Dipivefrin.
MirtazapineMirtazapine may decrease the antihypertensive activities of Dipivefrin.
NadololDipivefrin may increase the atrioventricular blocking (AV block) activities of Nadolol.
NaphazolineThe risk or severity of adverse effects can be increased when Naphazoline is combined with Dipivefrin.
NebivololDipivefrin may increase the atrioventricular blocking (AV block) activities of Nebivolol.
NorepinephrineThe risk or severity of adverse effects can be increased when Norepinephrine is combined with Dipivefrin.
NortriptylineThe therapeutic efficacy of Dipivefrin can be decreased when used in combination with Nortriptyline.
OrciprenalineThe risk or severity of adverse effects can be increased when Orciprenaline is combined with Dipivefrin.
OxymetazolineThe risk or severity of adverse effects can be increased when Oxymetazoline is combined with Dipivefrin.
PenbutololDipivefrin may increase the atrioventricular blocking (AV block) activities of Penbutolol.
PhenmetrazineThe risk or severity of adverse effects can be increased when Phenmetrazine is combined with Dipivefrin.
PhenoxybenzaminePhenoxybenzamine may decrease the vasoconstricting activities of Dipivefrin.
PhentermineThe risk or severity of adverse effects can be increased when Phentermine is combined with Dipivefrin.
PhentolaminePhentolamine may decrease the vasoconstricting activities of Dipivefrin.
PhenylephrineThe risk or severity of adverse effects can be increased when Phenylephrine is combined with Dipivefrin.
PhenylpropanolamineThe risk or severity of adverse effects can be increased when Phenylpropanolamine is combined with Dipivefrin.
PindololDipivefrin may increase the atrioventricular blocking (AV block) activities of Pindolol.
PrazosinPrazosin may decrease the vasoconstricting activities of Dipivefrin.
PropranololDipivefrin may increase the atrioventricular blocking (AV block) activities of Propranolol.
ProtriptylineThe therapeutic efficacy of Dipivefrin can be decreased when used in combination with Protriptyline.
RitodrineThe risk or severity of adverse effects can be increased when Ritodrine is combined with Dipivefrin.
SalmeterolThe risk or severity of adverse effects can be increased when Salmeterol is combined with Dipivefrin.
SilodosinSilodosin may decrease the vasoconstricting activities of Dipivefrin.
SotalolDipivefrin may increase the atrioventricular blocking (AV block) activities of Sotalol.
SpironolactoneSpironolactone may decrease the vasoconstricting activities of Dipivefrin.
TamsulosinTamsulosin may decrease the vasoconstricting activities of Dipivefrin.
Tedizolid PhosphateTedizolid Phosphate may increase the hypertensive activities of Dipivefrin.
TerazosinTerazosin may decrease the vasoconstricting activities of Dipivefrin.
TerbutalineThe risk or severity of adverse effects can be increased when Terbutaline is combined with Dipivefrin.
TimololDipivefrin may increase the atrioventricular blocking (AV block) activities of Timolol.
TrimipramineThe therapeutic efficacy of Dipivefrin can be decreased when used in combination with Trimipramine.
VenlafaxineVenlafaxine may decrease the antihypertensive activities of Dipivefrin.
Food InteractionsNot Available

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) proteins. Nuclear ADRA1A-ADRA1B heterooligomers regulate phenylephrine(PE)-stimulated ERK signaling in cardiac myocytes.
Gene Name:
ADRA1A
Uniprot ID:
P35348
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 oxymetazoline > clonidine > epinephrine > norepinephrine > phenylephrine > dopamine > p-synephrine > p-tyramine > serotonin = p-octopamine. For antagonists, the rank order is yohimbine > phentolamine = mianser...
Gene Name:
ADRA2A
Uniprot ID:
P08913
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 30-fold greater affinity than it does norepinephrine.
Gene Name:
ADRB2
Uniprot ID:
P07550
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
potentiator
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
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
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
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 ]
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Drug created on June 13, 2005 07:24 / Updated on August 17, 2016 12:23