Benserazide

Identification

Summary

Benserazide is a medication used to treat Parkinson's disease, parkinsonism, and restless leg syndrome.

Brand Names
Prolopa
Generic Name
Benserazide
DrugBank Accession Number
DB12783
Background

When levodopa is used by itself as a therapy for treating Parkinson's disease, its ubiquitous metabolism into dopamine is responsible for a resultant increase in the levels of circulating dopamine in the blood and to various extracerebral tissues. This can result in a number of side effects like nausea, vomiting, or even cardiac arrhythmias that may diminish patient adherence 3,2. A decarboxylase inhibitor like benserazide is consequently an effective compound to combine with levadopa as it is incapable of crossing the blood-brain barrier itself but acts to prevent the formation of dopamine from levadopa in extracerebral tissues - thereby acting to minimize the occurrence of extracerebral side effects 3,2.

Levodopa/benserazide combination products are used commonly worldwide for the management of Parkinson's disease. In particular, although the specific levodopa/benserazide combination is formally approved for use in Canada and much of Europe, the FDA has approved another similar levodopa/dopa decarboxylase inhibitor combination in the form of levodopa and carbidopa.

Moreover, the European Medcines Agency has conferred an orphan designation upon benseraside since 2015 for its potential to be used as a therapy for beta thalassaemia as well 4.

Type
Small Molecule
Groups
Approved, Investigational
Structure
Weight
Average: 257.246
Monoisotopic: 257.101170595
Chemical Formula
C10H15N3O5
Synonyms
  • benserazida
  • Benserazide
  • benserazidum
External IDs
  • RO 4-4602
  • RO-4-4602

Pharmacology

Indication

The primary therapeutic use for which benserazide is currently indicated for is as a combination therapy with levadopa for the treatment of Parkinson's disease in adults > 25 years of age, with the exception of drug-induced parkinsonism 3,2.

At certain doses, the combination product of levodopa and benserazide may also be used to treat restless legs syndrome, which is sometimes associated with Parkinson's disease 2,1.

There have also been some studies that have prompted the European Medicines Agency to confer orphan designation upon benserazide hydrochloride as a potential therapy for beta thalassaemia 4. Although studies are ongoing, no evidence has been formally elucidated as of yet 4.

Reduce drug development failure rates
Build, train, & validate machine-learning models
with evidence-based and structured datasets.
See how
Build, train, & validate predictive machine-learning models with structured datasets.
See how
Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Used in combination to manageParkinson's diseaseCombination Product in combination with: Levodopa (DB01235)••••••••••••
Contraindications & Blackbox Warnings
Prevent Adverse Drug Events Today
Tap into our Clinical API for life-saving information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.
Learn more
Avoid life-threatening adverse drug events with our Clinical API
Learn more
Pharmacodynamics

When used as a therapy for treating Parkinson's disease, levadopa's specific mechanism of action revolves around its metabolism into dopamine in the body 3,2. Unfortunately, the resultant increase in the levels of circulating dopamine in the blood and to various extracerebral tissues can result in a number of side effects like nausea, vomiting, or even cardiac arrhythmias that may diminish patient adherence 3,2. A decarboxylase inhibitor like benserazide is consequently an effective compound to combine with levadopa as it is incapable of crossing the blood-brain barrier itself and therefore allows levadopa to elicit its primary action in the central nervous system, but will prevent the formation of dopamine from levadopa in extracerebral tissues - thereby acting to minimize the occurrence of extracerebral side effects 3,2.

Mechanism of action

The combination of levodopa and benserazide is an anti-Parkinsonian agent 3,2. Levodopa itself is the metabolic precursor of dopamine. In Parkinson's disease, dopamine is depleted to a large degree in the striatum, pallidum, and substantia nigra in the central nervous system (CNS) 3,2. The administration of levodopa to treat the disease is subsequently proposed to facilitate raises in the levels of available dopamine in these areas 3,2. The metabolism of levodopa to dopamine occurs via the enzyme dopa decarboxylase, although unfortunately, this metabolism can also occur in extracerebral tissues 3,2. As a result, the full therapeutic effect of an administered dose of levodopa may not be obtained if portions of it are catabolized outside of the CNS and various patient adherence diminishing extracerebral side effects due to the extracerebral presence of dopamine like nausea, vomiting, or even cardiac arrhythmias can also happen 3,2.

Subsequently, a peripheral decarboxylase inhibitor like benserazide, which blocks the extracerebral decarboxylation of levodopa, when administered in combination with levodopa has obvious and significant advantages. Such benefits include reduced gastrointestinal side effects, a more rapid and complete response at the initiation of therapy, and a simpler dosing regimen 3,2.

It is important to note, however, that benserazide is hydroxylated to trihydroxybenzylhydrazine in the intestinal mucosa and the liver 3,2, and that as a potent inhibitor of the aromatic amino acid decarboxylase 3,2,1, it is this trihydroxybenzylhydrazine metabolite of benserazide that mainly protects levodopa against decarboxylation to dopamine in the gut and also around the rest of the body outside of the blood-brain barrier 1.

Regardless, because Parkinson's disease progresses even with the therapy of levodopa and benserazide, this kind of combined therapy is only ever indicated if it is capable of improving the quality of life and adverse effect profile of using such drugs for Parkinson's patients and there is little to be gained by switching to or starting this combination therapy if patients are already being managed with stable, effective, and well-tolerated levadopa-only therapy 3,2.

Finally, it is also proposed that benserazide hydrochloride may be able to treat beta thalassaemia by maintaining the active expression of the gene for fetal hemoglobin so that constant production of fetal hemoglobin may replace the missing adult hemoglobin variation that is characteristic of patients with the condition, thereby decreasing the need for blood transfusion therapy 4.

TargetActionsOrganism
AAromatic-L-amino-acid decarboxylase
inhibitor
Humans
Absorption

In a study, three patients were administered 50 mg of radiolabelled 14C-benserazide by both intravenous and oral routes 3,2. Three additional patients received oral doses of 50 mg 14C-benserazide alone 3,2. Comparison of the time-plasma concentration curves of total radioactivity in the patients receiving oral and intravenous 14C-benserazide indicated that between 66% and 74% of the administered dose was absorbed from the gastrointestinal tract 3,2. Peak plasma concentrations of radioactivity were detected one hour after oral administration in five of the six patients 3,2.

Volume of distribution

Readily accessible data regarding the volume of distribution of benserazide is not available 1.

Protein binding

Benserazide is observed as experiencing 0% protein binding 1.

Metabolism

Benserazide is hydroxylated to trihydroxybenzylhydrazine in the intestinal mucosa and the liver 3,2. Trihydroxybenzylhydrazine is a potent inhibitor of the aromatic acid decarboxylase 3,2, and it is believed that the levodopa in a levodopa/benserazide combination product is largely protected against decarboxylation mainly by way of this benserazide metabolite 1.

Hover over products below to view reaction partners

Route of elimination

Benserazide is rapidly excreted in the urine in the form of metabolites, mostly within the first 6 hours of administration, 85% of urinary excretion occurs within 12 hours 1.

Elimination of radiolabelled 14C-benserazide was primarily by urinary excretion with 86% to 90% of an intravenous dose recovered in the urine while 53% to 64% of an oral dose was detected in the urine 3,2. The majority of the 14C-benserazide was ultimately accounted for in the urine within 48 hours after administration 3,2. Fecal recovery studies conducted over five to eight days accounted for the majority (about 30%) of the remainder of the administered 14C-benserazide 3,2.

Ultimately, benserazide is almost entirely eliminated by metabolism 3,2. These metabolites are mainly excreted in the urine (64%) and to a smaller extent in the feces (24%) 3,2.

Half-life

The half-life of benserazide is documented as 1.5 hours 1.

Clearance

Readily accessible data regarding the clearance of benserazide is not available.

Adverse Effects
Improve decision support & research outcomes
With structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates. View sample adverse effects data in our new Data Library!
See the data
Improve decision support & research outcomes with our structured adverse effects data.
See a data sample
Toxicity

Overdosage may lead to cardiovascular side effects like cardiac arrhythmias, psychiatric disturbances like confusion and insomnia, gastrointestinal effects like nausea and vomiting, and abnormal involuntary movements 3,2.

Various LD50 values have been established for the rat model, including an oral LD50 of 5300 mg/kg in rats MSDS.

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbacavirAbacavir may decrease the excretion rate of Benserazide which could result in a higher serum level.
AceclofenacAceclofenac may decrease the excretion rate of Benserazide which could result in a higher serum level.
AcemetacinAcemetacin may decrease the excretion rate of Benserazide which could result in a higher serum level.
AcetaminophenAcetaminophen may decrease the excretion rate of Benserazide which could result in a higher serum level.
AcetazolamideAcetazolamide may increase the excretion rate of Benserazide which could result in a lower serum level and potentially a reduction in efficacy.
Food Interactions
  • Take with or without food. Benserazide is normally given in combination with levodopa as the combination product Prolopa. Levodopa should not be given with protein-rich foods as they may reduce its absorption.

Products

Drug product information from 10+ global regions
Our datasets provide approved product information including:
dosage, form, labeller, route of administration, and marketing period.
Access now
Access drug product information from over 10 global regions.
Access now
Product Ingredients
IngredientUNIICASInChI Key
Benserazide hydrochlorideB66E5RK36Q14919-77-8ULFCBIUXQQYDEI-UHFFFAOYSA-N
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
LEVOBENS TEVA 100MG/25MGBenserazide hydrochloride (28.54 mg) + Levodopa (100 mg)CapsuleOral2014-04-01Not applicableGermany flag
LEVODOPA BENS -CT 100MG/25Benserazide hydrochloride (28.54 mg) + Levodopa (100 mg)TabletOral2014-04-01Not applicableGermany flag
LEVODOPA BENS -CT 200MG/50Benserazide hydrochloride (57.09 mg) + Levodopa (200 mg)TabletOral2014-04-01Not applicableGermany flag
LEVODOPA BENS -CT50MG/12.5Benserazide hydrochloride (14.27 mg) + Levodopa (50 mg)TabletOral2014-04-01Not applicableGermany flag
LEVODOPA BENS BETA100/25MGBenserazide hydrochloride (28.54 mg) + Levodopa (100 mg)TabletOral2014-04-01Not applicableGermany flag

Categories

Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as serine and derivatives. These are compounds containing serine or a derivative thereof resulting from reaction of serine at the amino group or the carboxy group, or from the replacement of any hydrogen of glycine by a heteroatom.
Kingdom
Organic compounds
Super Class
Organic acids and derivatives
Class
Carboxylic acids and derivatives
Sub Class
Amino acids, peptides, and analogues
Direct Parent
Serine and derivatives
Alternative Parents
5-unsubstituted pyrrogallols / 1-hydroxy-4-unsubstituted benzenoids / 1-hydroxy-2-unsubstituted benzenoids / Benzene and substituted derivatives / Carboxylic acid hydrazides / Polyols / Primary alcohols / Organopnictogen compounds / Organic oxides / Monoalkylamines
show 2 more
Substituents
1-hydroxy-2-unsubstituted benzenoid / 1-hydroxy-4-unsubstituted benzenoid / 5-unsubstituted pyrrogallol / Alcohol / Amine / Aromatic homomonocyclic compound / Benzenetriol / Benzenoid / Carbonyl group / Carboxylic acid hydrazide
show 15 more
Molecular Framework
Aromatic homomonocyclic compounds
External Descriptors
carbohydrazide, catechols, primary alcohol, primary amino compound (CHEBI:64187)
Affected organisms
Not Available

Chemical Identifiers

UNII
762OS3ZEJU
CAS number
322-35-0
InChI Key
BNQDCRGUHNALGH-UHFFFAOYSA-N
InChI
InChI=1S/C10H15N3O5/c11-6(4-14)10(18)13-12-3-5-1-2-7(15)9(17)8(5)16/h1-2,6,12,14-17H,3-4,11H2,(H,13,18)
IUPAC Name
2-amino-3-hydroxy-N'-[(2,3,4-trihydroxyphenyl)methyl]propanehydrazide
SMILES
NC(CO)C(=O)NNCC1=C(O)C(O)=C(O)C=C1

References

General References
  1. Caroline Ashley, Aileen Dunleavy (2017). The Renal Drug Handbook: The Ultimate Prescribing Guide for Renal Practitioners (4th ed.). CRC Press. [ISBN:1498794610]
  2. Electronic Medicines Compendium: Madopar (levodopa/benserazide hydrochloride) 200mg/50mg Hard Capsules Monograph [Link]
  3. Roche Canada Product Monograph: Prolopa [File]
  4. European Medicines Agency Public Summary of Opinion on Orphan Designation: Benserazide Hydrochloride for the Treatment of Beta Thalassaemia Intermedia and Major [File]
  5. AGNP Consensus Guidelines for Therapeutic Drug Monitoring in Psychiatry: Update 2011 [File]
KEGG Drug
D03082
PubChem Compound
2327
PubChem Substance
347828964
ChemSpider
2237
BindingDB
49122
RxNav
1374
ChEBI
64187
ChEMBL
CHEMBL1096979
PharmGKB
PA165360203
Wikipedia
Benserazide
MSDS
Download (25.4 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedNot AvailableHealthy Volunteers (HV)1
4CompletedTreatmentParkinson's Disease (PD)1
3CompletedTreatmentParkinson's Disease (PD)2
3CompletedTreatmentRestless Legs Syndrome (RLS)1
2CompletedTreatmentParkinson's Disease (PD)3

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
TabletOral
Tablet; tablet, film coatedOral
Tablet, solubleOral
Capsule, extended releaseOral
CapsuleOral28.5 mg
TabletOral50 mg
TabletOral25 mg
CapsuleOral25 mg
Capsule, delayed releaseOral
Tablet, for solution; tablet, for suspensionOral
CapsuleOral
Prices
Not Available
Patents
Not Available

Properties

State
Not Available
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility5.15 mg/mLALOGPS
logP-2.3ALOGPS
logP-1.9Chemaxon
logS-1.7ALOGPS
pKa (Strongest Acidic)8.66Chemaxon
pKa (Strongest Basic)7.48Chemaxon
Physiological Charge1Chemaxon
Hydrogen Acceptor Count7Chemaxon
Hydrogen Donor Count7Chemaxon
Polar Surface Area148.07 Å2Chemaxon
Rotatable Bond Count5Chemaxon
Refractivity73.23 m3·mol-1Chemaxon
Polarizability24.49 Å3Chemaxon
Number of Rings1Chemaxon
Bioavailability1Chemaxon
Rule of FiveNoChemaxon
Ghose FilterNoChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleNoChemaxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSsplash10-03di-9410000000-042a7ca62eb315395c77
LC-MS/MS Spectrum - LC-ESI-QFT , negativeLC-MS/MSsplash10-00kr-0900000000-36834aa07db9235c3d01
LC-MS/MS Spectrum - LC-ESI-QFT , negativeLC-MS/MSsplash10-000i-1900000000-8d4a2c0c0f171ebdfaf2
LC-MS/MS Spectrum - LC-ESI-QFT , negativeLC-MS/MSsplash10-000i-3900000000-43ed8993954a8a907fb7
LC-MS/MS Spectrum - LC-ESI-QFT , negativeLC-MS/MSsplash10-052r-4900000000-30c8b3fbb72c084ed088
LC-MS/MS Spectrum - LC-ESI-QFT , negativeLC-MS/MSsplash10-0a4r-4900000000-d37ca07746ea74f04793
LC-MS/MS Spectrum - LC-ESI-QFT , negativeLC-MS/MSsplash10-0a4i-4900000000-9ecd00c168fa7c0fbbd8
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-00di-0900000000-147a530b86fcb416278a
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-000i-5900000000-37e67e92809b1668705e
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-000i-7900000000-ce0ce4287ecbaecc1e1a
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-000i-9600000000-ab3f3ce953e99425942e
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-0m53-3920000000-01e57b4b578de265bdcc
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-0670-1930000000-88e1f8e21910ef8b0bed
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-0w90-9820000000-3f729746c3df5e47775b
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-0079-2900000000-83c198e44c60273efb34
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-0006-9300000000-92d7a92179b64dd44bc0
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-000g-9720000000-59e8882650f65e5f4ae0
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-161.41017
predicted
DeepCCS 1.0 (2019)
[M+H]+163.76817
predicted
DeepCCS 1.0 (2019)
[M+Na]+169.86133
predicted
DeepCCS 1.0 (2019)

Targets

Build, predict & validate machine-learning models
Use our structured and evidence-based datasets to unlock new
insights and accelerate drug research.
Learn more
Use our structured and evidence-based datasets to unlock new insights and accelerate drug research.
Learn more
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Pyridoxal phosphate binding
Specific Function
Catalyzes the decarboxylation of L-3,4-dihydroxyphenylalanine (DOPA) to dopamine, L-5-hydroxytryptophan to serotonin and L-tryptophan to tryptamine.
Gene Name
DDC
Uniprot ID
P20711
Uniprot Name
Aromatic-L-amino-acid decarboxylase
Molecular Weight
53925.815 Da

Drug created at October 21, 2016 00:13 / Updated at February 21, 2021 18:53