- Accession Number
- Small Molecule
- Approved, Investigational
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.
- External IDs
- RO 4-4602 / RO-4-4602
- Product Ingredients
Ingredient UNII CAS InChI Key Benserazide hydrochloride B66E5RK36Q 14919-77-8 ULFCBIUXQQYDEI-UHFFFAOYSA-N
- Mixture Products
Name Ingredients Dosage Route Labeller Marketing Start Marketing End Prolopa Cap 100-25 Benserazide (25 mg) + Levodopa (100 mg) Capsule Oral Hoffmann La Roche 1977-12-31 Not applicable Prolopa Cap 200-50 Benserazide (50 mg) + Levodopa (200 mg) Capsule Oral Hoffmann La Roche 1977-12-31 Not applicable Prolopa Cap 50-12.5 Benserazide (12.5 mg) + Levodopa (50 mg) Capsule Oral Hoffmann La Roche 1981-12-31 Not applicable
- CAS number
- Average: 257.246
- Chemical Formula
- InChI Key
- IUPAC Name
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.
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
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.
Target Actions Organism AAromatic-L-amino-acid decarboxylaseinhibitor Humans
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.
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.
- Half life
The half-life of benserazide is documented as 1.5 hours 1.
Readily accessible data regarding the clearance of benserazide is not available.
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
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Comprehensive structured data on known drug adverse effects with statistical prevalence. MedDRA and ICD10 ids are provided for adverse effect conditions and symptoms.Learn more
Structured data covering drug contraindications. Each contraindication describes a scenario in which the drug is not to be used. Includes restrictions on co-administration, contraindicated populations, and more.Learn more
Structured data representing warnings from the black box section of drug labels. These warnings cover important and dangerous risks, contraindications, or adverse effects.Learn more
- 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.
Drug Interaction Abacavir Abacavir may decrease the excretion rate of Benserazide which could result in a higher serum level. Acarbose Acarbose may decrease the excretion rate of Benserazide which could result in a higher serum level. Aceclofenac Aceclofenac may decrease the excretion rate of Benserazide which could result in a higher serum level. Acemetacin Acemetacin may decrease the excretion rate of Benserazide which could result in a higher serum level. Acetaminophen Acetaminophen may decrease the excretion rate of Benserazide which could result in a higher serum level. Acetazolamide Acetazolamide may increase the excretion rate of Benserazide which could result in a lower serum level and potentially a reduction in efficacy. Acetylsalicylic acid Acetylsalicylic acid may decrease the excretion rate of Benserazide which could result in a higher serum level. Aclidinium Aclidinium may decrease the excretion rate of Benserazide which could result in a higher serum level. Acrivastine Acrivastine may decrease the excretion rate of Benserazide which could result in a higher serum level. Acyclovir Acyclovir may decrease the excretion rate of Benserazide which could result in a higher serum level.Additional Data Available
- Extended DescriptionExtended Description
Extended description of the mechanism of action and particular properties of each drug interaction.Learn more
A severity rating for each drug interaction, from minor to major.Learn more
- Evidence LevelEvidence Level
A rating for the strength of the evidence supporting each drug interaction.Learn more
An effect category for each drug interaction. Know how this interaction affects the subject drug.Learn more
- 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.
- General References
- Caroline Ashley, Aileen Dunleavy (2017). The Renal Drug Handbook: The Ultimate Prescribing Guide for Renal Practitioners (4th ed.). CRC Press. [ISBN:1498794610]
- Electronic Medicines Compendium: Madopar (levodopa/benserazide hydrochloride) 200mg/50mg Hard Capsules Monograph [Link]
- Roche Canada Product Monograph: Prolopa [File]
- European Medicines Agency Public Summary of Opinion on Orphan Designation: Benserazide Hydrochloride for the Treatment of Beta Thalassaemia Intermedia and Major [File]
- AGNP Consensus Guidelines for Therapeutic Drug Monitoring in Psychiatry: Update 2011 [File]
- External Links
- Download (25.4 KB)
- Clinical Trials
Phase Status Purpose Conditions Count 0 Completed Basic Science Healthy Volunteers / Schizotypal Personality 1 1 Completed Treatment Parkinson's Disease (PD) 4 3 Completed Treatment Parkinson's Disease (PD) 2 3 Completed Treatment Restless Legs Syndrome (RLS) 1 4 Completed Not Available Healthy Volunteers 1 4 Completed Treatment Parkinson's Disease (PD) 1 Not Available Completed Treatment Aphasia 1
- Not Available
- Not Available
- Dosage forms
Form Route Strength Capsule Oral
- Not Available
- Not Available
- Not Available
- Experimental Properties
- Not Available
- Predicted Properties
Property Value Source Water Solubility 5.15 mg/mL ALOGPS logP -2.3 ALOGPS logP -1.9 ChemAxon logS -1.7 ALOGPS pKa (Strongest Acidic) 8.66 ChemAxon pKa (Strongest Basic) 7.48 ChemAxon Physiological Charge 1 ChemAxon Hydrogen Acceptor Count 7 ChemAxon Hydrogen Donor Count 7 ChemAxon Polar Surface Area 148.07 Å2 ChemAxon Rotatable Bond Count 5 ChemAxon Refractivity 73.23 m3·mol-1 ChemAxon Polarizability 24.49 Å3 ChemAxon Number of Rings 1 ChemAxon Bioavailability 1 ChemAxon Rule of Five No ChemAxon Ghose Filter No ChemAxon Veber's Rule No ChemAxon MDDR-like Rule No ChemAxon
- Predicted ADMET features
- Not Available
- Mass Spec (NIST)
- Not Available
- 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.
- Organic compounds
- Super Class
- Organic acids and derivatives
- 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 / MonoalkylaminesHydrocarbon derivatives / Carbonyl compounds show 2 more
- 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 hydrazidePolyol / Alcohol / Primary amine / Primary alcohol / Hydrocarbon derivative / Organic oxide / Organooxygen compound / Organonitrogen compound / Primary aliphatic amine / Organopnictogen compound / Carbonyl group / Organic oxygen compound / Organic nitrogen compound / Amine / Aromatic homomonocyclic compound show 15 more
- Molecular Framework
- Aromatic homomonocyclic compounds
- External Descriptors
- carbohydrazide, catechols, primary alcohol, primary amino compound (CHEBI:64187)
- Pharmacological action
- 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
- Uniprot ID
- Uniprot Name
- Aromatic-L-amino-acid decarboxylase
- Molecular Weight
- 53925.815 Da
Drug created on October 20, 2016 18:13 / Updated on May 16, 2020 15:52