Identification

Name
Milrinone
Accession Number
DB00235  (APRD00010)
Type
Small Molecule
Groups
Approved
Description

A positive inotropic cardiotonic agent with vasodilator properties. It inhibits cAMP phosphodiesterase activity in myocardium and vascular smooth muscle. Milrinone is a derivative of amrinone and has 20-30 times the ionotropic potency of amrinone. [PubChem]

Structure
Thumb
Synonyms
  • 1,6-Dihydro-2-methyl-6-oxo(3,4'-bipyridine)-5-carbonitrile
  • Milrinona
  • Milrinone
  • Milrinonum
External IDs
WIN 47,203-2
Product Ingredients
IngredientUNIICASInChI Key
Milrinone Lactate9K8XR81MO8100286-97-3VWUPWEAFIOQCGF-UHFFFAOYSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Milrinone InjectionSolution1 mgIntravenousTeva2003-05-252015-07-22Canada
Milrinone Lactate InjectionSolution1 mgIntravenousMylan PharmaceuticalsNot applicableNot applicableCanada
Milrinone Lactate InjectionSolution1.0 mgIntravenousSandoz Canada Incorporated2003-06-25Not applicableCanada
Milrinone Lactate InjectionSolution1 mgIntravenousFresenius Kabi2003-07-03Not applicableCanada
Milrinone Lactate InjectionSolution1 mgIntravenousSterimax IncNot applicableNot applicableCanada
Milrinone Lactate InjectionSolution1 mgIntravenousAuro Pharma IncNot applicableNot applicableCanada
Primacor Injection 1mg/mlSolution1 mgIntravenousSanofi Synthelabo1995-12-312005-08-01Canada
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Apo-milrinone InjectableSolution1.0 mgIntravenousApotex Corporation2005-07-292013-08-02Canada
Milrinone LactateInjection, solution50 mg/50mLIntravenousWest Ward Pharmaceutical2010-12-03Not applicableUs
Milrinone LactateInjection, solution1 mg/1mLIntravenousHikma Farmaceutica2010-12-032010-12-03Us
Milrinone LactateInjection, solution1 mg/1mLIntravenousFresenius Kabi2002-08-01Not applicableUs
Milrinone LactateInjection, solution200 ug/1mLIntravenousHikma Farmaceutica2010-01-212010-01-21Us
Milrinone LactateInjection1 mg/1mLIntravenousBedford Pharmaceuticals2002-05-272011-10-31Us
Milrinone LactateInjection, solution1 mg/1mLIntravenousHospira Worldwide, Inc.2002-05-282009-04-05Us
Milrinone LactateInjection, solution1 mg/1mLIntravenousTeva Parenteral Medicines, Inc.2003-06-202005-04-30Us
Milrinone LactateInjection, solution1 mg/1mLIntravenousWest-Ward Pharmaceuticals Corp2010-12-03Not applicableUs
Milrinone LactateInjection1 mg/1mLIntravenousBedford Pharmaceuticals2002-05-272012-02-29Us
Unapproved/Other Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
Milrinone LactateMilrinone Lactate (1 mg/1mL)Injection, solutionIntravenousHospira, Inc.2006-07-172006-07-17Us
Milrinone Lactate in DextroseMilrinone Lactate (200 ug/1mL) + D-glucose monohydrate (49.4 mg/1mL)InjectionIntravenousB. Braun Medical Inc.2007-10-29Not applicableUs
Milrinone Lactate in DextroseMilrinone Lactate (200 ug/1mL)InjectionIntravenousBaxter Healthcare Corporation2006-07-272006-07-27Us
PrimacorMilrinone Lactate (1 mg/1mL)Injection, solutionIntravenousSanofi-Synthelabo Inc.2006-05-10Not applicableUs
PrimacorMilrinone Lactate (200 ug/1mL)Injection, solutionIntravenousSanofi-Synthelabo Inc.2006-05-10Not applicableUs
International/Other Brands
Corotrop / Corotrope / Milrila / Primacor
Categories
UNII
JU9YAX04C7
CAS number
78415-72-2
Weight
Average: 211.2194
Monoisotopic: 211.074561925
Chemical Formula
C12H9N3O
InChI Key
PZRHRDRVRGEVNW-UHFFFAOYSA-N
InChI
InChI=1S/C12H9N3O/c1-8-11(9-2-4-14-5-3-9)6-10(7-13)12(16)15-8/h2-6H,1H3,(H,15,16)
IUPAC Name
6-methyl-2-oxo-5-(pyridin-4-yl)-1,2-dihydropyridine-3-carbonitrile
SMILES
CC1=C(C=C(C#N)C(=O)N1)C1=CC=NC=C1

Pharmacology

Indication

Indicated for the treatment of congestive heart failure.

Associated Conditions
Pharmacodynamics

Milrinone, a synthetic dimethylxanthine derivative structurally related to theophylline and caffeine, is used in the treatment of peripheral vascular diseases and in the management of cerebrovascular insufficiency, sickle cell disease, and diabetic neuropathy.

Mechanism of action

Milrinone inhibits erythrocyte phosphodiesterase, resulting in an increase in erythrocyte cAMP activity. Subsequently, the erythrocyte membrane becomes more resistant to deformity. Along with erythrocyte activity, Milrinone also decreases blood viscosity by reducing plasma fibrinogen concentrations and increasing fibrinolytic activity.

TargetActionsOrganism
AcGMP-inhibited 3',5'-cyclic phosphodiesterase A
inhibitor
Human
Absorption

Milrinone is rapidly and almost completely absorbed after oral administration. Bioavailability is 92% (in healthy volunteers).

Volume of distribution
  • 0.38 liters/kg [intravenous injections of 12.5 mcg/kg to 125 mcg/kg to congestive heart failure patients]
  • 0.45 liters/kg [intravenous infusions of 0.20 mcg/kg/min to 0.70 mcg/kg/min to congestive heart failure patients]
Protein binding

70 to 80%

Metabolism

There are five metabolites but the O-glucuronide represents the major pathway of biotransformation.

Route of elimination

The primary route of excretion of milrinone in man is via the urine.

Half life

2.3 hours

Clearance
  • 0.13 L/kg/hr [congestive heart failure patients, following IV injections of 12.5 mcg/kg to 125 mcg/kg]
  • 0.14 L/kg/hr [congestive heart failure patients, following infusions of 0.2 mcg/kg/min to 0.7 mcg/kg/min]
Toxicity

LD50 = 0.3 mg/L in rats

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

Interactions

Drug Interactions
DrugInteraction
AbacavirMilrinone may decrease the excretion rate of Abacavir which could result in a higher serum level.
AcarboseMilrinone may decrease the excretion rate of Acarbose which could result in a higher serum level.
AceclofenacAceclofenac may decrease the excretion rate of Milrinone which could result in a higher serum level.
AcemetacinAcemetacin may decrease the excretion rate of Milrinone which could result in a higher serum level.
AcetaminophenMilrinone may decrease the excretion rate of Acetaminophen which could result in a higher serum level.
AcetarsolMilrinone may decrease the excretion rate of Acetarsol which could result in a higher serum level.
Acetylsalicylic acidAcetylsalicylic acid may decrease the excretion rate of Milrinone which could result in a higher serum level.
AclidiniumMilrinone may decrease the excretion rate of Aclidinium which could result in a higher serum level.
AcrivastineMilrinone may decrease the excretion rate of Acrivastine which could result in a higher serum level.
AcyclovirAcyclovir may decrease the excretion rate of Milrinone which could result in a higher serum level.
Food Interactions
Not Available

References

General References
Not Available
External Links
Human Metabolome Database
HMDB0014380
KEGG Drug
D00417
KEGG Compound
C07224
PubChem Compound
4197
PubChem Substance
46507838
ChemSpider
4052
BindingDB
15296
ChEBI
50693
ChEMBL
CHEMBL189
Therapeutic Targets Database
DAP000150
PharmGKB
PA164749171
HET
MIL
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Milrinone
ATC Codes
C01CE02 — Milrinone
AHFS Codes
  • 24:04.08 — Cardiotonic Agents
PDB Entries
1tlm
FDA label
Download (491 KB)
MSDS
Download (34.8 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentEnd Stage Heart Disease / Right Ventricular Dysfunction1
1, 2Active Not RecruitingTreatmentHeart Failure, Unspecified1
1, 2CompletedTreatmentHealthy Volunteers / Heart Failure, Unspecified1
1, 2CompletedTreatmentLow Cardiac Output Syndrome1
1, 2CompletedTreatmentPulmonary Hypertension (PH)1
1, 2WithdrawnTreatmentMyocardial Reperfusion Injury1
2CompletedPreventionDefect, Congenital Heart1
2CompletedPreventionPulmonary Hypertension (PH)1
2CompletedTreatmentCoronary Artery Disease / Pulmonary Hypertension (PH) / Valvular Insufficiency / Valvular Stenosis1
2Not Yet RecruitingTreatmentHeart Failure, Unspecified / Prophylaxis of cardiomyopathy1
2RecruitingTreatmentCongenital Diaphragmatic Hernias / Hypoplasia, Pulmonary / Hypoxemic Respiratory Failure / Persistent Pulmonary Hypertension of the Newborn1
2RecruitingTreatmentCongenital Heart Disease (CHD)1
2TerminatedTreatmentCerebral Vasospasm1
2TerminatedTreatmentHeart Defects,Congenital1
2Unknown StatusTreatmentLow Cardiac Output Syndrome1
2WithdrawnTreatmentCardiorenal Syndrome1
3CompletedTreatmentCardiac Output, Low1
3CompletedTreatmentMitral Valve Insufficiency / Pulmonary Hypertension (PH)1
4RecruitingTreatmentAcute Coronary Syndromes (ACS) / Low Cardiac Output Syndrome / Pulmonary Edemas / Shock, Cardiogenic1
4RecruitingTreatmentProphylaxis of cardiomyopathy / Shock, Septic1
Not AvailableCompletedPreventionComplication of Extracorporeal Circulation / Kidney Circulation Disorder / Renal Function Disorder1
Not AvailableCompletedTreatmentAcute Kidney Injury (AKI)1
Not AvailableCompletedTreatmentAortic Valve Stenosis / Heart Failure, Diastolic / Physiologic Monitoring / Physiology1
Not AvailableCompletedTreatmentCongenital Cardiovascular Defects / Low Cardiac Output Syndrome1
Not AvailableCompletedTreatmentHepatectomy1
Not AvailableRecruitingNot AvailableHeart Failure, Unspecified1
Not AvailableRecruitingPreventionArterial Hypotension1
Not AvailableTerminatedTreatmentPersistent Fetal Circulation Syndrome / Persistent Pulmonary Hypertension of Newborn (PPHN)1

Pharmacoeconomics

Manufacturers
  • App pharmaceuticals llc
  • Baxter healthcare corp anesthesia and critical care
  • Baxter healthcare corp anesthesia critical care
  • Bedford laboratories div ben venue laboratories inc
  • Bioniche pharma usa llc
  • Claris lifesciences ltd
  • Gland pharma ltd
  • Hospira inc
  • International medicated systems ltd
  • B braun medical inc
  • Baxter healthcare corp
  • Bedford laboratories
  • Hikma farmaceutica (portugal) sa
  • Sanofi aventis us llc
Packagers
  • Alchymars SPA
  • Apotex Inc.
  • APP Pharmaceuticals
  • B. Braun Melsungen AG
  • Baxter International Inc.
  • Bedford Labs
  • Ben Venue Laboratories Inc.
  • Bioniche Pharma
  • Cardinal Health
  • Hospira Inc.
  • Sanofi-Aventis Inc.
  • Teva Pharmaceutical Industries Ltd.
Dosage forms
FormRouteStrength
InjectionIntravenous1 mg/1mL
InjectionIntravenous20 mg/100mL
Injection, solutionIntravenous10 mg/10mL
Injection, solutionIntravenous20 mg/20mL
Injection, solutionIntravenous50 mg/50mL
InjectionIntravenous
InjectionIntravenous200 ug/1mL
Injection, solutionIntravenous0.2 mg/1mL
SolutionIntravenous1.0 mg
Injection, solutionIntravenous1 mg/1mL
Injection, solutionIntravenous200 ug/1mL
SolutionIntravenous1 mg
Prices
Unit descriptionCostUnit
Primacor 0.2 mg/ml-d5w 100 ml1.6USD ml
Milrinone-d5w 20 mg/100 ml1.45USD ml
Milrinone lact 20 mg/20 ml vial1.44USD ml
Milrinone lact 10 mg/10 ml vial1.31USD 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)>300 °CPhysProp
water solubilitySlightly solubleNot Available
logP0.4Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.209 mg/mLALOGPS
logP1.04ALOGPS
logP0.33ChemAxon
logS-3ALOGPS
pKa (Strongest Acidic)7.54ChemAxon
pKa (Strongest Basic)4.82ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area65.78 Å2ChemAxon
Rotatable Bond Count1ChemAxon
Refractivity61.14 m3·mol-1ChemAxon
Polarizability21.46 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+1.0
Blood Brain Barrier+0.9807
Caco-2 permeable+0.6889
P-glycoprotein substrateNon-substrate0.8041
P-glycoprotein inhibitor INon-inhibitor0.7835
P-glycoprotein inhibitor IINon-inhibitor0.9799
Renal organic cation transporterNon-inhibitor0.8614
CYP450 2C9 substrateNon-substrate0.7016
CYP450 2D6 substrateNon-substrate0.8411
CYP450 3A4 substrateNon-substrate0.5641
CYP450 1A2 substrateInhibitor0.5399
CYP450 2C9 inhibitorNon-inhibitor0.9071
CYP450 2D6 inhibitorNon-inhibitor0.9816
CYP450 2C19 inhibitorNon-inhibitor0.9025
CYP450 3A4 inhibitorNon-inhibitor0.8827
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.7866
Ames testNon AMES toxic0.7822
CarcinogenicityNon-carcinogens0.9351
BiodegradationNot ready biodegradable0.993
Rat acute toxicity2.5820 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.991
hERG inhibition (predictor II)Non-inhibitor0.8941
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
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSNot Available
LC-MS/MS Spectrum - LC-ESI-QQ , negativeLC-MS/MSsplash10-03di-0090000000-1894d0a48fc2ccb74718
LC-MS/MS Spectrum - LC-ESI-QQ , negativeLC-MS/MSsplash10-03di-0190000000-6ae34a9fd604b709bcc9
LC-MS/MS Spectrum - LC-ESI-QQ , negativeLC-MS/MSsplash10-03di-0970000000-c1a7f68e4f0eb27d6881
LC-MS/MS Spectrum - LC-ESI-QQ , negativeLC-MS/MSsplash10-014i-1900000000-8e2c336e4e2425cca486
LC-MS/MS Spectrum - LC-ESI-QQ , negativeLC-MS/MSsplash10-014i-3900000000-047756d13498358fc54d
LC-MS/MS Spectrum - LC-ESI-QQ , positiveLC-MS/MSsplash10-01ta-1910000000-c2df049a2cac6a6ad313
LC-MS/MS Spectrum - LC-ESI-QQ , positiveLC-MS/MSsplash10-03dj-3910000000-21cb0ac7a539590cf3a5
LC-MS/MS Spectrum - LC-ESI-QQ , positiveLC-MS/MSsplash10-08n9-7900000000-f774999fc6fb39238858
LC-MS/MS Spectrum - LC-ESI-QQ , positiveLC-MS/MSsplash10-00o1-9300000000-9b1eed78c20489183326
LC-MS/MS Spectrum - LC-ESI-QQ , positiveLC-MS/MSsplash10-004l-9100000000-c84b782dfa6c28c15ddc
LC-MS/MS Spectrum - LC-ESI-IT , positiveLC-MS/MSsplash10-001i-0900000000-969f8d74389284d0c167
MS/MS Spectrum - , positiveLC-MS/MSsplash10-03di-0790000000-fe6863cad241275fc104

Taxonomy

Description
This compound belongs to the class of organic compounds known as bipyridines and oligopyridines. These are organic compounds containing two pyridine rings linked to each other.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Pyridines and derivatives
Sub Class
Bipyridines and oligopyridines
Direct Parent
Bipyridines and oligopyridines
Alternative Parents
3-pyridinecarbonitriles / Methylpyridines / Hydroxypyridines / Heteroaromatic compounds / Nitriles / Azacyclic compounds / Organopnictogen compounds / Organooxygen compounds / Hydrocarbon derivatives
Substituents
Bipyridine / 3-pyridinecarbonitrile / Methylpyridine / Hydroxypyridine / Heteroaromatic compound / Azacycle / Nitrile / Carbonitrile / Organic nitrogen compound / Organic oxygen compound
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
nitrile, pyridone, bipyridines (CHEBI:50693)

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
Uniprot Name
cGMP-inhibited 3',5'-cyclic phosphodiesterase A
Molecular Weight
124978.06 Da
References
  1. Cone J, Wang S, Tandon N, Fong M, Sun B, Sakurai K, Yoshitake M, Kambayashi J, Liu Y: Comparison of the effects of cilostazol and milrinone on intracellular cAMP levels and cellular function in platelets and cardiac cells. J Cardiovasc Pharmacol. 1999 Oct;34(4):497-504. [PubMed:10511123]
  2. Kuthe A, Magert H, Uckert S, Forssmann WG, Stief CG, Jonas U: Gene expression of the phosphodiesterases 3A and 5A in human corpus cavernosum penis. Eur Urol. 2000 Jul;38(1):108-14. [PubMed:10859452]
  3. Lefievre L, de Lamirande E, Gagnon C: Presence of cyclic nucleotide phosphodiesterases PDE1A, existing as a stable complex with calmodulin, and PDE3A in human spermatozoa. Biol Reprod. 2002 Aug;67(2):423-30. [PubMed:12135876]
  4. Zhang W, Ke H, Colman RW: Identification of interaction sites of cyclic nucleotide phosphodiesterase type 3A with milrinone and cilostazol using molecular modeling and site-directed mutagenesis. Mol Pharmacol. 2002 Sep;62(3):514-20. [PubMed:12181427]
  5. Shakur Y, Fong M, Hensley J, Cone J, Movsesian MA, Kambayashi J, Yoshitake M, Liu Y: Comparison of the effects of cilostazol and milrinone on cAMP-PDE activity, intracellular cAMP and calcium in the heart. Cardiovasc Drugs Ther. 2002 Sep;16(5):417-27. [PubMed:12652111]
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]

Drug created on June 13, 2005 07:24 / Updated on September 25, 2018 03:01