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Details

Stereochemistry RACEMIC
Molecular Formula C13H24O5
Molecular Weight 260.3267
Optical Activity ( + / - )
Defined Stereocenters 0 / 1
E/Z Centers 0
Charge 0
Stereo Comments Assumed racemic

SHOW SMILES / InChI
Structure of 1-(ETHOXYCARBONYLOXY)ETHYL VALPROATE

SMILES

CCCC(CCC)C(=O)OC(C)OC(=O)OCC

InChI

InChIKey=ZIJGGSZJPPURSY-UHFFFAOYSA-N
InChI=1S/C13H24O5/c1-5-8-11(9-6-2)12(14)17-10(4)18-13(15)16-7-3/h10-11H,5-9H2,1-4H3

HIDE SMILES / InChI

Molecular Formula C13H24O5
Molecular Weight 260.3267
Charge 0
Count
Stereochemistry RACEMIC
Additional Stereochemistry No
Defined Stereocenters 0 / 1
E/Z Centers 0
Optical Activity ( + / - )

Description
Curator's Comment: Description was created based on several sources, including http://psychopharmacologyinstitute.com/mood-stabilizers/valproate-in-psychiatry-approved-indications-and-off-label-uses/ | https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/022152s002lbl.pdf | https://www.ncbi.nlm.nih.gov/pubmed/12847559 | https://www.ncbi.nlm.nih.gov/pubmed/11742974 | https://www.ncbi.nlm.nih.gov/pubmed/11473107

Valproic acid (VPA; valproate; di-n-propylacetic acid, DPA; 2-propylpentanoic acid, or 2-propylvaleric acid) was first synthesized in 1882, by Burton. FDA approved valproic acid for the treatment of manic episodes associated with bipolar disorder, for the monotherapy and adjunctive therapy of complex partial seizures and simple and complex absence seizures and adjunctive therapy in patients with multiple seizure types that include absence seizures and for the prophylaxis of migraine headaches. The mechanisms of VPA which seem to be of clinical importance in the treatment of epilepsy include increased gamma-aminobutyric acid (GABA)-ergic activity, reduction in excitatory neurotransmission, and modification of monoamines. Recently, it was discovered that the VPA is a class I selective histone deacetylase inhibitor. This activity can be distinguished from its therapeutically exploited antiepileptic activity.

Originator

Sources: Burton B.S. (1882) On the propyl derivatives and decomposition products of ethylacetoacetate. Am Chem J3: 385–395
Curator's Comment: reference retrieved from https://link.springer.com/chapter/10.1007%2F978-3-0348-8759-5_1

Approval Year

TargetsConditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
DEPAKENE

Approved Use

Depakene (valproic acid) is indicated as monotherapy and adjunctive therapy in the treatment of patients with complex partial seizures that occur either in isolation or in association with other types of seizures. Depakene (valproic acid) is indicated for use as sole and adjunctive therapy in the treatment of simple and complex absence seizures, and adjunctively in patients with multiple seizure types which include absence seizures. Simple absence is defined as very brief clouding of the sensorium or loss of consciousness accompanied by certain generalized epileptic discharges without other detectable clinical signs. Complex absence is the term used when other signs are also present.
Preventing
STAVZOR

Approved Use

Stavzor (valproic acid) delayed release capsules is indicated for: • Acute treatment of manic episodes associated with bipolar disorder • Monotherapy and adjunctive therapy of complex partial seizures and simple and complex absence seizures; adjunctive therapy in patients with multiple seizure types that include absence seizures • Prophylaxis of migraine headaches

Launch Date

2008
Primary
STAVZOR

Approved Use

Stavzor (valproic acid) delayed release capsules is indicated for: • Acute treatment of manic episodes associated with bipolar disorder • Monotherapy and adjunctive therapy of complex partial seizures and simple and complex absence seizures; adjunctive therapy in patients with multiple seizure types that include absence seizures • Prophylaxis of migraine headaches

Launch Date

2008
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
107.2 mg/L
500 mg 2 times / day multiple, oral
dose: 500 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
VALPROIC ACID plasma
Homo sapiens
population: HEALTHY
age: UNKNOWN
sex: FEMALE / MALE
food status: FED
AUC

AUC

ValueDoseCo-administeredAnalytePopulation
1951 mg × h/L
500 mg 2 times / day multiple, oral
dose: 500 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
VALPROIC ACID plasma
Homo sapiens
population: HEALTHY
age: UNKNOWN
sex: FEMALE / MALE
food status: FED
T1/2

T1/2

ValueDoseCo-administeredAnalytePopulation
16 h
1000 mg 1 times / day steady-state, oral
dose: 1000 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
VALPROIC ACID unknown
Homo sapiens
population: UNKNOWN
age: UNKNOWN
sex: UNKNOWN
food status: UNKNOWN
Doses

Doses

DosePopulationAdverse events​
150 mg/kg single, intravenous
Highest studied dose
Dose: 150 mg/kg
Route: intravenous
Route: single
Dose: 150 mg/kg
Sources: Page: p.6
healthy, 30.2 ± 11.7
n = 3
Health Status: healthy
Age Group: 30.2 ± 11.7
Sex: M+F
Population Size: 3
Sources: Page: p.6
DLT: Headache, Nausea...
Dose limiting toxicities:
Headache
Nausea
Sources: Page: p.6
140 mg/kg single, intravenous
MTD
Dose: 140 mg/kg
Route: intravenous
Route: single
Dose: 140 mg/kg
Sources: Page: p.6
healthy, 30.2 ± 11.7
n = 6
Health Status: healthy
Age Group: 30.2 ± 11.7
Sex: M+F
Population Size: 6
Sources: Page: p.6
25 g single, oral
Overdose
Dose: 25 g
Route: oral
Route: single
Dose: 25 g
Sources: Page: p.1
unhealthy, 37
n = 1
Health Status: unhealthy
Condition: Seizures |Bipolar disorder
Age Group: 37
Sex: M
Population Size: 1
Sources: Page: p.1
Disc. AE: Somnolence...
AEs leading to
discontinuation/dose reduction:
Somnolence
Sources: Page: p.1
100 g single, oral
Overdose
Dose: 100 g
Route: oral
Route: single
Dose: 100 g
Sources: Page: 110000
unhealthy, 41
n = 1
Health Status: unhealthy
Condition: Epilepsy
Age Group: 41
Sex: M
Population Size: 1
Sources: Page: 110000
Disc. AE: Coma...
AEs leading to
discontinuation/dose reduction:
Coma
Sources: Page: 110000
120 mg/kg 1 times / day multiple, intravenous
Highest studied dose
Dose: 120 mg/kg, 1 times / day
Route: intravenous
Route: multiple
Dose: 120 mg/kg, 1 times / day
Sources: Page: p.179
unhealthy, 62.5
n = 5
Health Status: unhealthy
Condition: Cancer
Age Group: 62.5
Sex: M+F
Population Size: 5
Sources: Page: p.179
DLT: Somnolence...
Dose limiting toxicities:
Somnolence (40%)
Sources: Page: p.179
60 mg/kg 1 times / day multiple, intravenous
MTD
Dose: 60 mg/kg, 1 times / day
Route: intravenous
Route: multiple
Dose: 60 mg/kg, 1 times / day
Sources: Page: p.178
unhealthy, 62.5
n = 3
Health Status: unhealthy
Condition: Cancer
Age Group: 62.5
Sex: M+F
Population Size: 3
Sources: Page: p.178
60 mg/kg 1 times / day multiple, oral
Recommended
Dose: 60 mg/kg, 1 times / day
Route: oral
Route: multiple
Dose: 60 mg/kg, 1 times / day
Sources: Page: p.1
unhealthy
Health Status: unhealthy
Condition: Seizures
Sources: Page: p.1
Disc. AE: Hepatotoxicity, Pancreatitis...
AEs leading to
discontinuation/dose reduction:
Hepatotoxicity
Pancreatitis
Sources: Page: p.1
AEs

AEs

AESignificanceDosePopulation
Headache DLT
150 mg/kg single, intravenous
Highest studied dose
Dose: 150 mg/kg
Route: intravenous
Route: single
Dose: 150 mg/kg
Sources: Page: p.6
healthy, 30.2 ± 11.7
n = 3
Health Status: healthy
Age Group: 30.2 ± 11.7
Sex: M+F
Population Size: 3
Sources: Page: p.6
Nausea DLT
150 mg/kg single, intravenous
Highest studied dose
Dose: 150 mg/kg
Route: intravenous
Route: single
Dose: 150 mg/kg
Sources: Page: p.6
healthy, 30.2 ± 11.7
n = 3
Health Status: healthy
Age Group: 30.2 ± 11.7
Sex: M+F
Population Size: 3
Sources: Page: p.6
Somnolence Disc. AE
25 g single, oral
Overdose
Dose: 25 g
Route: oral
Route: single
Dose: 25 g
Sources: Page: p.1
unhealthy, 37
n = 1
Health Status: unhealthy
Condition: Seizures |Bipolar disorder
Age Group: 37
Sex: M
Population Size: 1
Sources: Page: p.1
Coma Disc. AE
100 g single, oral
Overdose
Dose: 100 g
Route: oral
Route: single
Dose: 100 g
Sources: Page: 110000
unhealthy, 41
n = 1
Health Status: unhealthy
Condition: Epilepsy
Age Group: 41
Sex: M
Population Size: 1
Sources: Page: 110000
Somnolence 40%
DLT
120 mg/kg 1 times / day multiple, intravenous
Highest studied dose
Dose: 120 mg/kg, 1 times / day
Route: intravenous
Route: multiple
Dose: 120 mg/kg, 1 times / day
Sources: Page: p.179
unhealthy, 62.5
n = 5
Health Status: unhealthy
Condition: Cancer
Age Group: 62.5
Sex: M+F
Population Size: 5
Sources: Page: p.179
Hepatotoxicity Disc. AE
60 mg/kg 1 times / day multiple, oral
Recommended
Dose: 60 mg/kg, 1 times / day
Route: oral
Route: multiple
Dose: 60 mg/kg, 1 times / day
Sources: Page: p.1
unhealthy
Health Status: unhealthy
Condition: Seizures
Sources: Page: p.1
Pancreatitis Disc. AE
60 mg/kg 1 times / day multiple, oral
Recommended
Dose: 60 mg/kg, 1 times / day
Route: oral
Route: multiple
Dose: 60 mg/kg, 1 times / day
Sources: Page: p.1
unhealthy
Health Status: unhealthy
Condition: Seizures
Sources: Page: p.1
Overview

Overview

Drug as perpetrator​

Drug as perpetrator​

TargetModalityActivityMetaboliteClinical evidence
minimal
minimal
minimal
no
weak [Ki 7975 uM]
weak [Ki 8553 uM]
weak [Ki 9150 uM]
yes [Ki 600 uM]
likely (co-administration study)
Comment: competitive inhibition; risk of pharmacokinetic drug–drug interactions should be taken into account during concomitant use of valproic acid and CYP2C9 substrates
Drug as victim
PubMed

PubMed

TitleDatePubMed
Sodium valproate (Epilim) in epilepsy: a trial.
1978 Dec 27
Influence of adenosine agonists and antiepileptic drugs on theophylline-induced seizures in rats.
1998 Oct
Assessment of colour vision in epileptic patients exposed to single-drug therapy.
1999
Adding lamotrigine to valproate: incidence of rash and other adverse effects. Postmarketing Antiepileptic Drug Survey (PADS) Group.
1999 Aug
N-acetyl-beta-glucosaminidase and beta-galactosidase activity in children receiving antiepileptic drugs.
1999 Jan
Cognitive dysfunction induced by phenytoin and valproate in rats: effect of nitric oxide.
1999 Jul
Fatal liver failure associated with valproate therapy in a patient with Friedreich's disease: review of valproate hepatotoxicity in adults.
1999 Jul
Risperidone-induced mania.
1999 Mar
Anticonvulsants for soman-induced seizure activity.
1999 Mar-Apr
[Lyell syndrome associated with lamotrigine].
2000 Dec 16-31
Orthotopic liver transplantation with poor neurologic outcome in valproate-associated liver failure: a need for critical risk-benefit appraisal in the use of valproate.
2000 Feb
Sodium valproate inhibits production of TNF-alpha and IL-6 and activation of NF-kappaB.
2000 Feb 28
Valproic acid-induced alterations in growth and neurotrophic factor gene expression in murine embryos [corrected].
2000 Jan-Feb
Valproic acid-induced hyperammonemic encephalopathy with triphasic waves.
2000 Jul
Testosterone abuse and affective disorders.
2000 Mar
In vivo study of the effect of valpromide and valnoctamide in the pilocarpine rat model of focal epilepsy.
2000 Nov
A case of pharmacokinetic interference in comedication of clozapine and valproic acid.
2000 Nov
The safety of rapid valproic acid infusion.
2000 Oct
Vitamin E decreases valproic acid induced neural tube defects in mice.
2000 Oct 13
Action of valproic acid on Xenopus laevis development: teratogenic effects on eyes.
2001
Probenecid-associated alterations in valproate glucuronide hepatobiliary disposition: mechanistic assessment using mathematical modeling.
2001 Apr
Determination of the antiepileptics vigabatrin and gabapentin in dosage forms and biological fluids using Hantzsch reaction.
2001 Feb
Collaborative study on rat sperm motion analysis using CellSoft Series 4000 semen analyzer.
2001 Feb
A case of chronic pancreatic insufficiency due to valproic acid in a child.
2001 Feb
Melt pelletization of a hygroscopic drug in a high shear mixer. Part 3. Effects of binder variation.
2001 Feb
Effect of coadministered drugs and ethanol on the binding of therapeutic drugs to human serum in vitro.
2001 Feb
Divalproex sodium augmentation of haloperidol in hospitalized patients with schizophrenia: clinical and economic implications.
2001 Feb
Different control of GH secretion by gamma-amino- and gamma-hydroxy-butyric acid in 4-year abstinent alcoholics.
2001 Feb 1
Evaluating the tolerability of the newer mood stabilizers.
2001 Jan
Occurrence of thrombocytopenia in psychiatric patients taking valproate.
2001 Jan
[Febrile pleuropericarditis during valproic acid treatment].
2001 Jan 20
Mood-stabilisers reduce the risk of developing antidepressant-induced maniform states in acute treatment of bipolar I depressed patients.
2001 Mar
Patents

Sample Use Guides

Usual Adult Dose for Epilepsy Complex partial seizures: Initial dose: 10 to 15 mg/kg orally or intravenously per day as an IV infusion in divided doses, increased by 5 to 10 mg/kg per week if necessary according to clinical response Maintenance dose: 10 to 60 mg/kg per day in divided doses Maximum dose: 60 mg/kg per day Simple and complex absence seizures: Initial dose: 15 mg/kg orally or intravenously per day as an IV infusion in divided doses, increased at one week intervals by 5 to 10 mg/kg/day according to seizure control and tolerability Maximum dose: 60 mg/kg per day Comments: -If the total daily dose exceeds 250 mg, it should be given in 2 to 3 divided doses. -Use of IV valproate sodium for periods longer than 14 days has not been studied; patients should be converted to oral valproate as soon as clinically feasible. -When switching from oral to IV valproate, the total daily dose of IV valproate should be equivalent to the total daily dose of oral valproate, and administered at the same frequency as the oral product. -Equivalence between IV and oral valproate products at steady state has only been evaluated in a 6-hourly dosing regimen. Trough plasma level monitoring may be required if IV valproate is administered 2 to 3 times a day. -Complex partial seizures: When converting patients to valproate monotherapy, concomitant antiepileptic drug dosage can generally be reduced by approximately 25% every 2 weeks, commencing either at the start of valproate therapy or delayed by 1 to 2 weeks. Patients should be monitored closely during this period for increased seizure frequency. Uses: Monotherapy and adjunctive therapy in the treatment of complex partial seizures; sole and adjunctive therapy for simple and complex absence seizures; adjunctive therapy in patients with multiple seizure types that include absence seizures. Usual Adult Dose for Mania Delayed-release capsules : Initial dose: 750 mg orally per day in divided doses Maximum dose: 60 mg/kg orally per day Duration: Safety and efficacy beyond 3 weeks has not been established Comments: -The dose should be increased as rapidly as possible to achieve the lowest therapeutic dose which produces the desired clinical effect or the desired range of plasma concentrations. -In placebo-controlled clinical trials of acute mania, patients were dosed to a clinical response with a trough plasma concentration of 50 to 125 mcg/mL. -Maximum concentrations were generally achieved within 14 days. -Safety and efficacy for longer term use in the maintenance of the initial response and prevention of new manic episodes has not been systematically evaluated in clinical trials. Use for extended periods should be accompanied by regular review for the long-term usefulness of the drug for the individual patient. Use: Treatment of manic episodes associated with bipolar disorder. Usual Adult Dose for Migraine Prophylaxis Delayed release oral capsules: Initial dose: 250 mg orally twice a day Comments: -Some patients may benefit from doses up to 1000 mg per day. -In clinical trials, there was no evidence that higher doses led to greater efficacy. Usual Pediatric Dose for Epilepsy 10 years of age or older: Complex partial seizures: Initial dose: 10 to 15 mg/kg orally or intravenously per day as an IV infusion in divided doses, increased by 5 to 10 mg/kg per week if necessary according to clinical response Maintenance dose: 10 to 60 mg/kg per day in divided doses Maximum dose: 60 mg/kg per day Simple and complex absence seizures: Initial dose: 15 mg/kg orally or intravenously per day as an IV infusion in divided doses, increased at one week intervals by 5 to 10 mg/kg/day according to seizure control and tolerability Maximum dose: 60 mg/kg per day Comments: -If the total daily dose exceeds 250 mg, it should be given in 2 to 3 divided doses. -Use of IV valproate sodium for periods longer than 14 days has not been studied; patients should be converted to oral valproate as soon as clinically feasible. -When switching from oral to IV valproate, the total daily dose of IV valproate should be equivalent to the total daily dose of oral valproate, and administered at the same frequency as the oral product. -Equivalence between IV and oral valproate products at steady state has only been evaluated in a 6-hourly dosing regimen. Trough plasma level monitoring may be required if IV valproate is administered 2 to 3 times a day. -Complex partial seizures: When converting patients to valproate monotherapy, concomitant antiepileptic drug dosage can generally be reduced by approximately 25% every 2 weeks, commencing either at the start of valproate therapy or delayed by 1 to 2 weeks. Patients should be monitored closely during this period for increased seizure frequency. Uses: Monotherapy and adjunctive therapy in the treatment of complex partial seizures; sole and adjunctive therapy for simple and complex absence seizures; adjunctive therapy in patients with multiple seizure types that include absence seizures.
Route of Administration: Other
H9C2 cells were cultured and allotted to the blank, vehicle, and valproic acid (VPA)-treated groups: the VPA treated group received VPA exposure at concentrations of 2.0, 4.0 and 8.0 mmol/L. VPA might result in acetylation/deacetylation imbalances by inhibiting HDAC1-3 protein expression and total HDAC activity, leading to the down-regulation of mRNA and protein expression of Vangl2 and Scrib.
Substance Class Chemical
Created
by admin
on Fri Dec 15 15:11:10 GMT 2023
Edited
by admin
on Fri Dec 15 15:11:10 GMT 2023
Record UNII
D9VW6400WJ
Record Status Validated (UNII)
Record Version
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Name Type Language
1-(ETHOXYCARBONYLOXY)ETHYL VALPROATE
Common Name English
VALDICE
Brand Name English
PENTANOIC ACID, 2-PROPYL-, 1-((ETHOXYCARBONYL)OXY)ETHYL ESTER
Systematic Name English
Code System Code Type Description
FDA UNII
D9VW6400WJ
Created by admin on Fri Dec 15 15:11:10 GMT 2023 , Edited by admin on Fri Dec 15 15:11:10 GMT 2023
PRIMARY
PUBCHEM
185249
Created by admin on Fri Dec 15 15:11:10 GMT 2023 , Edited by admin on Fri Dec 15 15:11:10 GMT 2023
PRIMARY
EPA CompTox
DTXSID70918628
Created by admin on Fri Dec 15 15:11:10 GMT 2023 , Edited by admin on Fri Dec 15 15:11:10 GMT 2023
PRIMARY
CAS
93181-78-3
Created by admin on Fri Dec 15 15:11:10 GMT 2023 , Edited by admin on Fri Dec 15 15:11:10 GMT 2023
PRIMARY
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