Actions of Benserazide/levodopa in details
ATC Code: N04BA.
Pharmacology: Pharmacodynamics: Mechanism of Action: Dopamine, which acts as a neurotransmitter in the brain, is not present in sufficient quantities in the basal ganglia of Parkinsonian patients. Levodopa (INN) or L-DOPA (3,4-dihydroxy L-phenylalanine) is an intermediate in dopamine biosynthesis. Levodopa (dopamine precursor) is used as a prodrug to increase dopamine levels since it is able to cross the blood-brain barrier whereas dopamine itself cannot. Once levodopa has entered the central nervous system (CNS), it is metabolized to dopamine by aromatic L-amino acid decarboxylase.
After administration, levodopa is rapidly decarboxylated to dopamine in extracerebral as well as cerebral tissues. As a result, most of the levodopa administered is not available to the basal ganglia and the dopamine produced peripherally frequently causes unwanted effects. It is therefore, particularly desirable to inhibit extracerebral decarboxylation of levodopa. This can be achieved by simultaneous administration of levodopa and benserazide, a peripheral decarboxylase inhibitor.
Benserazide/levodopa is a combination of these 2 substances in a ratio of 4:1. This ratio having proved optimal in clinical trials and therapeutic use and is just as effective as large doses of levodopa given alone.
Pharmacokinetics: Absorption: Standard Forms: Levodopa is mainly absorbed from the upper regions of the small intestine and absorption there is independent of the site. Maximum plasma concentrations of levodopa are reached approximately 1 hr after ingestion of standard Benserazide/levodopa.
Capsules and tablets of standard Benserazide/levodopa are bioequivalent.
The maximum plasma concentration of levodopa and the extent of levodopa absorption [area under the concentration-time curve (AUC)] increase proportionally with dose (levodopa 50-200 mg).
Food intake reduces the rate and extent of levodopa absorption. The peak levodopa plasma concentration is 30% lower and occurs later when standard Benserazide/levodopa is administered after a standard meal. The extent of levodopa absorption is reduced by 15%.
Dispersible Form: The pharmacokinetic profiles of levodopa following administration of Benserazide/levodopa dispersible in healthy volunteers and Parkinsonian patients are very similar to those following administration of standard Benserazide/levodopa, but time to peak concentrations tends to be shorter after Benserazide/levodopa dispersible. There is less interindividual variability in absorption parameters for Benserazide/levodopa dispersible taken as a suspension.
Controlled-Release Form: The pharmacokinetic properties of Benserazide/levodopa HBS differ from those of standard Benserazide/levodopa (capsules, tablets) and dispersible form. The active ingredients are released slowly in the stomach. Maximum plasma concentrations of levodopa, which are 20-30% of those achieved with the standard dosage forms, are reached about 3 hrs after administration. The AUC shows a longer 'half-value duration' (time span during which plasma concentrations are equal to or exceed half the maximum concentration) than with standard Benserazide/levodopa, which indicates pronounced controlled-release properties. The bioavailability of Benserazide/levodopa HBS is 50-70% of that of standard Benserazide/levodopa and is not affected by food. Maximum plasma concentrations of levodopa are not affected by food, but occur later (5 hrs) after postprandial administration of Benserazide/levodopa HBS.
Distribution: Levodopa crosses the blood-brain barrier by a saturable transport system. It is not bound to plasma proteins and its volume of distribution is 57 L. The AUC of levodopa in cerebrospinal fluid is 12% of that in plasma.
In contrast to levodopa, benserazide does not penetrate the blood-brain barrier at therapeutic doses. It is concentrated mainly in the kidneys, lungs, small intestine and liver.
Metabolism: Levodopa is metabolized by 2 major pathways (decarboxylation and O-methylation) and 2 minor ones (transamination and oxidation).
Aromatic amino acid decarboxylase converts levodopa to dopamine. The major end-products of this pathway are homovanillic acid and dihydroxyphenylacetic acid. Catechol-O-methyltransferase methylates levodopa to 3-O-methyldopa. This major plasma metabolite has an elimination half-life (t½) of 15 hrs, and it accumulates in patients who receive therapeutic doses of Benserazide/levodopa.
Decreased peripheral decarboxylation of levodopa when it is administered with benserazide is reflected in higher plasma levels of levodopa and 3-O-methyldopa and lower plasma levels of catecholamines (dopamine, noradrenaline) and phenolcarboxylic acids (homovanillic acid, dihydroxyphenylacetic acid).
Benserazide is hydroxylated to trihydroxybenzylhydrazine in the intestinal mucosa and the liver. This metabolite is a potent inhibitor of the aromatic amino acid decarboxylase.
Elimination: In the presence of peripherally inhibited levodopa decarboxylase the elimination t½ of levodopa is approximately 1.5 hrs. The elimination t½ is slightly longer (approximately 25%) in elderly patients (65-78 years) with Parkinson's disease. The clearance of levodopa from plasma is about 430 mL/min.
Benserazide is almost entirely eliminated by metabolism. The metabolites are mainly excreted in the urine (64%) and to a smaller extent in feces (24%).
Special Populations: No pharmacokinetic data are available in uremic and hepatic patients.
Effect of Age on the Pharmacokinetics of Levodopa: In older Parkinsonian patients (65-78 years) both the elimination t½ and the AUC of levodopa is about 25% higher than in younger patients (34-64 years). The statistically significant age effect is clinically negligible and is of minor importance for the dosing schedule of any indication.
Toxicology: Preclinical Safety Data: Carcinogenicity: Carcinogenicity studies were not conducted with Benserazide/levodopa.
Mutagenicity: Benserazide/levodopa and its constituents (levodopa and benserazide) were not observed to be mutagenic in the Ames test. No further data are available.
Impairment of Fertility: No animal studies on fertility were performed with Benserazide/levodopa.
Teratogenicity: Teratogenicity studies showed no teratogenic effects or effects on skeletal development in mice [400 mg/kg; rats (600 mg/kg; 250 mg/kg) and rabbits (120 mg/kg; 150 mg/kg)].
At maternally toxic dose levels, intrauterine deaths increased (rabbits) and/or fetal weight decreased (rats).
Other: General toxicological studies in rats have shown the possibility of disturbed skeletal development.
No further animal data of relevance are available.
Benserazide/levodopa pharmacology
Sulfonylureas such as Benserazide/levodopa likely bind to ATP-sensitive potassium-channel receptors on the pancreatic cell surface, reducing potassium conductance and causing depolarization of the membrane. Depolarization stimulates calcium ion influx through voltage-sensitive calcium channels, raising intracellular concentrations of calcium ions, which induces the secretion, or exocytosis, of insulin.
References
- DailyMed. "CARBIDOPA; ENTACAPONE; LEVODOPA: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailyme... (accessed September 17, 2018).
- NCIt. "Levodopa: NCI Thesaurus (NCIt) provides reference terminology for many systems. It covers vocabulary for clinical care, translational and basic research, and public information and administrative activities.". https://ncit.nci.nih.gov/ncitbrowser... (accessed September 17, 2018).
- EPA DSStox. "L-Dopa: DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology.". https://comptox.epa.gov/dashboard/ds... (accessed September 17, 2018).
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Information checked by Dr. Sachin Kumar, MD Pharmacology
