Identification

Name
Benserazide
Accession Number
DB12783
Type
Small Molecule
Groups
Approved, Investigational
Description

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].

Structure
Thumb
Synonyms
  • benserazida
  • benserazidum
External IDs
RO 4-4602 / RO-4-4602
Product Ingredients
IngredientUNIICASInChI Key
Benserazide hydrochlorideB66E5RK36Q14919-77-8ULFCBIUXQQYDEI-UHFFFAOYSA-N
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
Prolopa Cap 100-25Benserazide (25 mg) + Levodopa (100 mg)CapsuleOralHoffmann La Roche1977-12-31Not applicableCanada
Prolopa Cap 200-50Benserazide (50 mg) + Levodopa (200 mg)CapsuleOralHoffmann La Roche1977-12-31Not applicableCanada
Prolopa Cap 50-12.5Benserazide (12.5 mg) + Levodopa (50 mg)CapsuleOralHoffmann La Roche1981-12-31Not applicableCanada
Categories
UNII
762OS3ZEJU
CAS number
322-35-0
Weight
Average: 257.246
Monoisotopic: 257.101170595
Chemical Formula
C10H15N3O5
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

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].

Associated Conditions
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
Human
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].

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.

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].

Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
AbacavirAbacavir may decrease the excretion rate of Benserazide which could result in a higher serum level.
AcarboseAcarbose 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.
Acetylsalicylic acidAcetylsalicylic acid may decrease the excretion rate of Benserazide which could result in a higher serum level.
AclidiniumAclidinium may decrease the excretion rate of Benserazide which could result in a higher serum level.
AcrivastineAcrivastine may decrease the excretion rate of Benserazide which could result in a higher serum level.
AcyclovirAcyclovir may decrease the excretion rate of Benserazide which could result in a higher serum level.
AdefovirAdefovir may decrease the excretion rate of Benserazide which could result in a higher serum level.
Food Interactions
Not Available

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]
External Links
KEGG Drug
D03082
PubChem Compound
2327
PubChem Substance
347828964
ChemSpider
2237
BindingDB
49122
ChEBI
64187
ChEMBL
CHEMBL1096979
PharmGKB
PA165360203
Wikipedia
Benserazide
MSDS
Download (25.4 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentParkinson's Disease (PD)3
3CompletedTreatmentParkinson's Disease (PD)2
4CompletedNot AvailableHealthy Volunteers1
Not AvailableCompletedTreatmentAphasia1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
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-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-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

Taxonomy

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
Serine or derivatives / 5-unsubstituted pyrrogallol / Benzenetriol / Pyrogallol derivative / 1-hydroxy-4-unsubstituted benzenoid / 1-hydroxy-2-unsubstituted benzenoid / Phenol / Monocyclic benzene moiety / Benzenoid / Carboxylic acid hydrazide
show 15 more
Molecular Framework
Aromatic homomonocyclic compounds
External Descriptors
carbohydrazide, catechols, primary alcohol, primary amino compound (CHEBI:64187)

Targets

Kind
Protein
Organism
Human
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 on October 20, 2016 18:13 / Updated on November 02, 2018 09:14