Actions of Madopar LIQ 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 (Madopar LIQ) (INN) or L-DOPA (3,4-dihydroxy L-phenylalanine) is an intermediate in dopamine biosynthesis. Levodopa (Madopar LIQ) (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 (Madopar LIQ) has entered the central nervous system (CNS), it is metabolized to dopamine by aromatic L-amino acid decarboxylase.
After administration, Levodopa (Madopar LIQ) is rapidly decarboxylated to dopamine in extracerebral as well as cerebral tissues. As a result, most of the Levodopa (Madopar LIQ) 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 (Madopar LIQ). This can be achieved by simultaneous administration of Levodopa (Madopar LIQ) and Benserazide (Madopar LIQ), a peripheral decarboxylase inhibitor.
Madopar LIQ 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 (Madopar LIQ) given alone.
Pharmacokinetics: Absorption: Standard Forms: Levodopa (Madopar LIQ) is mainly absorbed from the upper regions of the small intestine and absorption there is independent of the site. Maximum plasma concentrations of Levodopa (Madopar LIQ) are reached approximately 1 hr after ingestion of standard Madopar LIQ.
Capsules and tablets of standard Madopar LIQ are bioequivalent.
The maximum plasma concentration of Levodopa (Madopar LIQ) and the extent of Levodopa (Madopar LIQ) absorption [area under the concentration-time curve (AUC)] increase proportionally with dose (Levodopa (Madopar LIQ) 50-200 mg).
Food intake reduces the rate and extent of Levodopa (Madopar LIQ) absorption. The peak Levodopa (Madopar LIQ) plasma concentration is 30% lower and occurs later when standard Madopar LIQ is administered after a standard meal. The extent of Levodopa (Madopar LIQ) absorption is reduced by 15%.
Dispersible Form: The pharmacokinetic profiles of Levodopa (Madopar LIQ) following administration of Madopar LIQ dispersible in healthy volunteers and Parkinsonian patients are very similar to those following administration of standard Madopar LIQ, but time to peak concentrations tends to be shorter after Madopar LIQ dispersible. There is less interindividual variability in absorption parameters for Madopar LIQ dispersible taken as a suspension.
Controlled-Release Form: The pharmacokinetic properties of Madopar LIQ HBS differ from those of standard Madopar LIQ (capsules, tablets) and dispersible form. The active ingredients are released slowly in the stomach. Maximum plasma concentrations of Levodopa (Madopar LIQ), 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 Madopar LIQ, which indicates pronounced controlled-release properties. The bioavailability of Madopar LIQ HBS is 50-70% of that of standard Madopar LIQ and is not affected by food. Maximum plasma concentrations of Levodopa (Madopar LIQ) are not affected by food, but occur later (5 hrs) after postprandial administration of Madopar LIQ HBS.
Distribution: Levodopa (Madopar LIQ) 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 (Madopar LIQ) in cerebrospinal fluid is 12% of that in plasma.
In contrast to Levodopa (Madopar LIQ), Benserazide (Madopar LIQ) does not penetrate the blood-brain barrier at therapeutic doses. It is concentrated mainly in the kidneys, lungs, small intestine and liver.
Metabolism: Levodopa (Madopar LIQ) is metabolized by 2 major pathways (decarboxylation and O-methylation) and 2 minor ones (transamination and oxidation).
Aromatic amino acid decarboxylase converts Levodopa (Madopar LIQ) to dopamine. The major end-products of this pathway are homovanillic acid and dihydroxyphenylacetic acid. Catechol-O-methyltransferase methylates Levodopa (Madopar LIQ) 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 Madopar LIQ.
Decreased peripheral decarboxylation of Levodopa (Madopar LIQ) when it is administered with Benserazide (Madopar LIQ) is reflected in higher plasma levels of Levodopa (Madopar LIQ) and 3-O-methyldopa and lower plasma levels of catecholamines (dopamine, noradrenaline) and phenolcarboxylic acids (homovanillic acid, dihydroxyphenylacetic acid).
Benserazide (Madopar LIQ) 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 (Madopar LIQ) decarboxylase the elimination t½ of Levodopa (Madopar LIQ) 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 (Madopar LIQ) from plasma is about 430 mL/min.
Benserazide (Madopar LIQ) 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 (Madopar LIQ): In older Parkinsonian patients (65-78 years) both the elimination t½ and the AUC of Levodopa (Madopar LIQ) 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 Madopar LIQ.
Mutagenicity: Madopar LIQ and its constituents (Levodopa (Madopar LIQ) and Benserazide (Madopar LIQ)) 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 Madopar LIQ.
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.
Madopar LIQ pharmacology
Sulfonylureas such as Madopar LIQ 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).
Reviews
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Information checked by Dr. Sachin Kumar, MD Pharmacology
