Identification

Name
Clevidipine
Accession Number
DB04920
Type
Small Molecule
Groups
Approved, Investigational
Description

Clevidipine is a dihydropyridine L-type calcium channel blocker that is selective for vascular smooth muscle and is indicated for blood pressure reduction when oral therapy is not an option.

Structure
Thumb
Synonyms
  • Clevidipine butyrate
  • Clevidipino
External IDs
H-324/38
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
CleviprexEmulsion0.5 mg/1mLIntravenousChiesi Pharmaceuticals Inc.2008-09-15Not applicableUs
CleviprexEmulsion0.5 mgIntravenousChiesi Farmaceutici S.P.A.Not applicableNot applicableCanada
CleviprexEmulsion0.5 mg/1mLIntravenousChiesi Pharmaceuticals Inc.2008-09-15Not applicableUs
CleviprexEmulsion0.5 mg/1mLIntravenousFresenius Kabi Austria GmbH2008-09-15Not applicableUs
CleviprexEmulsion0.5 mg/1mLIntravenousChiesi Pharmaceuticals Inc.2008-09-15Not applicableUs
CleviprexEmulsion0.5 mg/1mLIntravenousThe Medicines Company2008-09-15Not applicableUs
CleviprexEmulsion0.5 mg/1mLIntravenousThe Medicines Company2008-08-132008-08-13Us
Categories
UNII
19O2GP3B7Q
CAS number
167221-71-8
Weight
Average: 456.316
Monoisotopic: 455.090242887
Chemical Formula
C21H23Cl2NO6
InChI Key
KPBZROQVTHLCDU-UHFFFAOYSA-N
InChI
InChI=1S/C21H23Cl2NO6/c1-5-7-15(25)29-10-30-21(27)17-12(3)24-11(2)16(20(26)28-4)18(17)13-8-6-9-14(22)19(13)23/h6,8-9,18,24H,5,7,10H2,1-4H3
IUPAC Name
methyl 5-{[(butanoyloxy)methoxy]carbonyl}-4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylate
SMILES
CCCC(=O)OCOC(=O)C1=C(C)NC(C)=C(C1C1=CC=CC(Cl)=C1Cl)C(=O)OC

Pharmacology

Indication

For the treatment of hypertension.

Associated Conditions
Pharmacodynamics

Clevidipine belongs to a well-known class of drugs called dihydropyridine calcium channel antagonists. Clevidpine is the first third generation intravenous dihydropyridine calcium channel blocker. In vitro studies demonstrated that clevidipine acts by selectively relaxing the smooth muscle cells that line small arteries, resulting in arterial dilation, widening of the artery opening, and without reducing central venous pressure or reducing cardiac output.

Mechanism of action

Possibly by deforming the channel, inhibiting ion-control gating mechanisms, and/or interfering with the release of calcium from the sarcoplasmic reticulum, clevidipine inhibits the influx of extracellular calcium across both the myocardial and vascular smooth muscle cell membranes. The resultant inhibition of the contractile processes of the myocardial smooth muscle cells leads to dilation of the coronary and systemic arteries and improved oxygen delivery to the myocardial tissue.

TargetActionsOrganism
UVoltage-dependent L-type calcium channel subunit alpha-1FNot AvailableHuman
UVoltage-dependent L-type calcium channel subunit alpha-1SNot AvailableHuman
UVoltage-dependent L-type calcium channel subunit alpha-1DNot AvailableHuman
UVoltage-dependent L-type calcium channel subunit alpha-1CNot AvailableHuman
Absorption
Not Available
Volume of distribution
Not Available
Protein binding

>99.5%

Metabolism

Clevidipine is rapidly hydrolyzed to inactive metabolites by esterases in arterial blood.

Route of elimination

urine 63-74%, feces 7-22%

Half life

1 minute

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

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe metabolism of (R)-warfarin can be increased when combined with Clevidipine.
(S)-WarfarinThe metabolism of (S)-Warfarin can be increased when combined with Clevidipine.
2,4-thiazolidinedioneThe risk or severity of hypoglycemia can be increased when Clevidipine is combined with 2,4-thiazolidinedione.
3,5-diiodothyropropionic acidThe metabolism of 3,5-diiodothyropropionic acid can be increased when combined with Clevidipine.
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be increased when combined with Clevidipine.
4-MethoxyamphetamineThe metabolism of Clevidipine can be decreased when combined with 4-Methoxyamphetamine.
5-androstenedioneThe metabolism of 5-androstenedione can be increased when combined with Clevidipine.
6-Deoxyerythronolide BThe metabolism of Clevidipine can be decreased when combined with 6-Deoxyerythronolide B.
6-O-benzylguanineThe metabolism of 6-O-benzylguanine can be increased when combined with Clevidipine.
AbacavirAbacavir may decrease the excretion rate of Clevidipine which could result in a higher serum level.
Food Interactions
  • Grapefruit Juice

References

General References
  1. Zhang JG, Dehal SS, Ho T, Johnson J, Chandler C, Blanchard AP, Clark RJ Jr, Crespi CL, Stresser DM, Wong J: Human cytochrome p450 induction and inhibition potential of clevidipine and its primary metabolite h152/81. Drug Metab Dispos. 2006 May;34(5):734-7. Epub 2006 Feb 24. [PubMed:16501008]
  2. Nordlander M, Sjoquist PO, Ericsson H, Ryden L: Pharmacodynamic, pharmacokinetic and clinical effects of clevidipine, an ultrashort-acting calcium antagonist for rapid blood pressure control. Cardiovasc Drug Rev. 2004 Fall;22(3):227-50. [PubMed:15492770]
  3. Wang QD, Segawa D, Ericsson H, Sjoquist PO, Johansson L, Ryden L: Time-dependent cardioprotection with calcium antagonism and experimental studies with clevidipine in ischemic-reperfused pig hearts: part I. J Cardiovasc Pharmacol. 2002 Aug;40(2):228-34. [PubMed:12131552]
  4. Stephens CT, Jandhyala BS: Effects of fenoldopam, a dopamine D-1 agonist, and clevidipine, a calcium channel antagonist, in acute renal failure in anesthetized rats. Clin Exp Hypertens. 2002 May;24(4):301-13. [PubMed:12069360]
External Links
KEGG Drug
D08892
PubChem Compound
153994
PubChem Substance
175426904
ChemSpider
135722
ChEBI
135738
ChEMBL
CHEMBL1237132
Wikipedia
Clevidipine
ATC Codes
C08CA16 — Clevidipine
AHFS Codes
  • 24:28.08 — Dihydropyridines
FDA label
Download (381 KB)
MSDS
Download (568 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
0RecruitingBasic ScienceVascular Diseases1
2CompletedTreatmentHigh Blood Pressure (Hypertension)1
2Unknown StatusTreatmentCerebral Aneurysms / Subarachnoid Hemorrhage / Vasospasm, Intracranial1
2Unknown StatusTreatmentHigh Blood Pressure (Hypertension) / Subarachnoid Hemorrhage1
2, 3CompletedTreatmentNeuromuscular Scoliosis1
3CompletedTreatmentHeart Failure, Unspecified / High Blood Pressure (Hypertension)1
3CompletedTreatmentHemorrhage / High Blood Pressure (Hypertension)1
3CompletedTreatmentHigh Blood Pressure (Hypertension)6
4CompletedDiagnosticPulmonary Hypertension (PH)1
4CompletedTreatmentEpilepsies / High Blood Pressure (Hypertension) / Neoplasms, Brain1
4RecruitingTreatmentNontraumatic Intracerebral Hemorrhage, Multiple Localized1
4TerminatedTreatmentAortic Aneurysms / Aortic Diseases1
4Unknown StatusTreatmentPediatric Perioperative Blood Pressure Management1
4WithdrawnTreatmentHigh Blood Pressure (Hypertension)2
4WithdrawnTreatmentHigh Blood Pressure (Hypertension) / Intracranial Hemorrhages / Subarachnoid Hemorrhage1
Not AvailableWithdrawnTreatmentAorta Aneurysm / Dissection of Aorta1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
EmulsionIntravenous0.5 mg
EmulsionIntravenous0.5 mg/1mL
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US5739152No1995-04-142015-04-14Us
US5856346No2001-01-052021-01-05Us
US8658676No2011-10-102031-10-10Us
US10010537No2011-10-102031-10-10Us

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.00267 mg/mLALOGPS
logP4.98ALOGPS
logP4.09ChemAxon
logS-5.2ALOGPS
pKa (Strongest Basic)5.31ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area90.93 Å2ChemAxon
Rotatable Bond Count10ChemAxon
Refractivity113.93 m3·mol-1ChemAxon
Polarizability45.12 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9887
Blood Brain Barrier-0.5892
Caco-2 permeable+0.6566
P-glycoprotein substrateSubstrate0.5787
P-glycoprotein inhibitor IInhibitor0.8948
P-glycoprotein inhibitor IINon-inhibitor0.6827
Renal organic cation transporterNon-inhibitor0.8312
CYP450 2C9 substrateNon-substrate0.8879
CYP450 2D6 substrateNon-substrate0.8693
CYP450 3A4 substrateSubstrate0.693
CYP450 1A2 substrateInhibitor0.6871
CYP450 2C9 inhibitorInhibitor0.6818
CYP450 2D6 inhibitorNon-inhibitor0.8455
CYP450 2C19 inhibitorInhibitor0.7456
CYP450 3A4 inhibitorInhibitor0.9187
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.9098
Ames testNon AMES toxic0.7527
CarcinogenicityNon-carcinogens0.8407
BiodegradationNot ready biodegradable0.9403
Rat acute toxicity2.6248 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.7841
hERG inhibition (predictor II)Non-inhibitor0.8148
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 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
MS/MS Spectrum - , positiveLC-MS/MSsplash10-0059-0015900000-5d813bb035601f752e65
MS/MS Spectrum - , positiveLC-MS/MSsplash10-000l-0019000000-3e3b6549a7821bc27951

Taxonomy

Description
This compound belongs to the class of organic compounds known as dihydropyridinecarboxylic acids and derivatives. These are compounds containing a dihydropyridine moiety bearing a carboxylic acid group.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Pyridines and derivatives
Sub Class
Hydropyridines
Direct Parent
Dihydropyridinecarboxylic acids and derivatives
Alternative Parents
Tricarboxylic acids and derivatives / Dichlorobenzenes / Acylals / Fatty acid esters / Aryl chlorides / Vinylogous amides / Methyl esters / Enoate esters / Amino acids and derivatives / Acetals
show 8 more
Substituents
Dihydropyridinecarboxylic acid derivative / Tricarboxylic acid or derivatives / 1,2-dichlorobenzene / Chlorobenzene / Acylal / Fatty acid ester / Halobenzene / Aryl chloride / Aryl halide / Monocyclic benzene moiety
show 26 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Voltage-gated calcium channel activity
Specific Function
Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hor...
Gene Name
CACNA1F
Uniprot ID
O60840
Uniprot Name
Voltage-dependent L-type calcium channel subunit alpha-1F
Molecular Weight
220675.9 Da
References
  1. Nordlander M, Sjoquist PO, Ericsson H, Ryden L: Pharmacodynamic, pharmacokinetic and clinical effects of clevidipine, an ultrashort-acting calcium antagonist for rapid blood pressure control. Cardiovasc Drug Rev. 2004 Fall;22(3):227-50. [PubMed:15492770]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Voltage-gated calcium channel activity
Specific Function
Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hor...
Gene Name
CACNA1S
Uniprot ID
Q13698
Uniprot Name
Voltage-dependent L-type calcium channel subunit alpha-1S
Molecular Weight
212348.1 Da
References
  1. Nordlander M, Sjoquist PO, Ericsson H, Ryden L: Pharmacodynamic, pharmacokinetic and clinical effects of clevidipine, an ultrashort-acting calcium antagonist for rapid blood pressure control. Cardiovasc Drug Rev. 2004 Fall;22(3):227-50. [PubMed:15492770]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Voltage-gated calcium channel activity involved sa node cell action potential
Specific Function
Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hor...
Gene Name
CACNA1D
Uniprot ID
Q01668
Uniprot Name
Voltage-dependent L-type calcium channel subunit alpha-1D
Molecular Weight
245138.75 Da
References
  1. Nordlander M, Sjoquist PO, Ericsson H, Ryden L: Pharmacodynamic, pharmacokinetic and clinical effects of clevidipine, an ultrashort-acting calcium antagonist for rapid blood pressure control. Cardiovasc Drug Rev. 2004 Fall;22(3):227-50. [PubMed:15492770]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Voltage-gated calcium channel activity
Specific Function
Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hor...
Gene Name
CACNA1C
Uniprot ID
Q13936
Uniprot Name
Voltage-dependent L-type calcium channel subunit alpha-1C
Molecular Weight
248974.1 Da
References
  1. Nordlander M, Sjoquist PO, Ericsson H, Ryden L: Pharmacodynamic, pharmacokinetic and clinical effects of clevidipine, an ultrashort-acting calcium antagonist for rapid blood pressure control. Cardiovasc Drug Rev. 2004 Fall;22(3):227-50. [PubMed:15492770]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Steroid hydroxylase activity
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
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
References
  1. Zhang JG, Dehal SS, Ho T, Johnson J, Chandler C, Blanchard AP, Clark RJ Jr, Crespi CL, Stresser DM, Wong J: Human cytochrome p450 induction and inhibition potential of clevidipine and its primary metabolite h152/81. Drug Metab Dispos. 2006 May;34(5):734-7. Epub 2006 Feb 24. [PubMed:16501008]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic...
Gene Name
CYP2D6
Uniprot ID
P10635
Uniprot Name
Cytochrome P450 2D6
Molecular Weight
55768.94 Da
References
  1. Zhang JG, Dehal SS, Ho T, Johnson J, Chandler C, Blanchard AP, Clark RJ Jr, Crespi CL, Stresser DM, Wong J: Human cytochrome p450 induction and inhibition potential of clevidipine and its primary metabolite h152/81. Drug Metab Dispos. 2006 May;34(5):734-7. Epub 2006 Feb 24. [PubMed:16501008]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Metabolizes several precarcinogens, drugs, and solvents to reactive metabolites. Inactivates a number of drugs and xenobiotics and also bioactivates many xenobiotic substrates to their hepatotoxic ...
Gene Name
CYP2E1
Uniprot ID
P05181
Uniprot Name
Cytochrome P450 2E1
Molecular Weight
56848.42 Da
References
  1. Zhang JG, Dehal SS, Ho T, Johnson J, Chandler C, Blanchard AP, Clark RJ Jr, Crespi CL, Stresser DM, Wong J: Human cytochrome p450 induction and inhibition potential of clevidipine and its primary metabolite h152/81. Drug Metab Dispos. 2006 May;34(5):734-7. Epub 2006 Feb 24. [PubMed:16501008]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and im...
Gene Name
CYP2C19
Uniprot ID
P33261
Uniprot Name
Cytochrome P450 2C19
Molecular Weight
55930.545 Da
References
  1. Zhang JG, Dehal SS, Ho T, Johnson J, Chandler C, Blanchard AP, Clark RJ Jr, Crespi CL, Stresser DM, Wong J: Human cytochrome p450 induction and inhibition potential of clevidipine and its primary metabolite h152/81. Drug Metab Dispos. 2006 May;34(5):734-7. Epub 2006 Feb 24. [PubMed:16501008]
  2. Clevidipine FDA label [File]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
Inducer
General Function
Vitamin d3 25-hydroxylase activity
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 performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Zhang JG, Dehal SS, Ho T, Johnson J, Chandler C, Blanchard AP, Clark RJ Jr, Crespi CL, Stresser DM, Wong J: Human cytochrome p450 induction and inhibition potential of clevidipine and its primary metabolite h152/81. Drug Metab Dispos. 2006 May;34(5):734-7. Epub 2006 Feb 24. [PubMed:16501008]
  2. Uesawa Y, Takeuchi T, Mohri K: Integrated analysis on the physicochemical properties of dihydropyridine calcium channel blockers in grapefruit juice interactions. Curr Pharm Biotechnol. 2012 Jul;13(9):1705-17. [PubMed:22039822]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
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. Ericsson H, Tholander B, Regardh CG: In vitro hydrolysis rate and protein binding of clevidipine, a new ultrashort-acting calcium antagonist metabolised by esterases, in different animal species and man. Eur J Pharm Sci. 1999 Apr;8(1):29-37. [PubMed:10072476]

Drug created on October 21, 2007 16:23 / Updated on November 13, 2018 08:00