Actions of Madopar 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. Madopar (INN) or L-DOPA (3,4-dihydroxy L-phenylalanine) is an intermediate in dopamine biosynthesis. Madopar (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 Madopar has entered the central nervous system (CNS), it is metabolized to dopamine by aromatic L-amino acid decarboxylase.
After administration, Madopar is rapidly decarboxylated to dopamine in extracerebral as well as cerebral tissues. As a result, most of the Madopar 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 Madopar. This can be achieved by simultaneous administration of Madopar and Benserazide (Madopar), a peripheral decarboxylase inhibitor.
Madopar 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 Madopar given alone.
Pharmacokinetics: Absorption: Standard Forms: Madopar is mainly absorbed from the upper regions of the small intestine and absorption there is independent of the site. Maximum plasma concentrations of Madopar are reached approximately 1 hr after ingestion of standard Madopar.
Capsules and tablets of standard Madopar are bioequivalent.
The maximum plasma concentration of Madopar and the extent of Madopar absorption [area under the concentration-time curve (AUC)] increase proportionally with dose (Madopar 50-200 mg).
Food intake reduces the rate and extent of Madopar absorption. The peak Madopar plasma concentration is 30% lower and occurs later when standard Madopar is administered after a standard meal. The extent of Madopar absorption is reduced by 15%.
Dispersible Form: The pharmacokinetic profiles of Madopar following administration of Madopar dispersible in healthy volunteers and Parkinsonian patients are very similar to those following administration of standard Madopar, but time to peak concentrations tends to be shorter after Madopar dispersible. There is less interindividual variability in absorption parameters for Madopar dispersible taken as a suspension.
Controlled-Release Form: The pharmacokinetic properties of Madopar HBS differ from those of standard Madopar (capsules, tablets) and dispersible form. The active ingredients are released slowly in the stomach. Maximum plasma concentrations of Madopar, 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, which indicates pronounced controlled-release properties. The bioavailability of Madopar HBS is 50-70% of that of standard Madopar and is not affected by food. Maximum plasma concentrations of Madopar are not affected by food, but occur later (5 hrs) after postprandial administration of Madopar HBS.
Distribution: Madopar 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 Madopar in cerebrospinal fluid is 12% of that in plasma.
In contrast to Madopar, Benserazide (Madopar) does not penetrate the blood-brain barrier at therapeutic doses. It is concentrated mainly in the kidneys, lungs, small intestine and liver.
Metabolism: Madopar is metabolized by 2 major pathways (decarboxylation and O-methylation) and 2 minor ones (transamination and oxidation).
Aromatic amino acid decarboxylase converts Madopar to dopamine. The major end-products of this pathway are homovanillic acid and dihydroxyphenylacetic acid. Catechol-O-methyltransferase methylates Madopar 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.
Decreased peripheral decarboxylation of Madopar when it is administered with Benserazide (Madopar) is reflected in higher plasma levels of Madopar and 3-O-methyldopa and lower plasma levels of catecholamines (dopamine, noradrenaline) and phenolcarboxylic acids (homovanillic acid, dihydroxyphenylacetic acid).
Benserazide (Madopar) 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 Madopar decarboxylase the elimination t½ of Madopar 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 Madopar from plasma is about 430 mL/min.
Benserazide (Madopar) 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 Madopar: In older Parkinsonian patients (65-78 years) both the elimination t½ and the AUC of Madopar 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.
Mutagenicity: Madopar and its constituents (Madopar and Benserazide (Madopar)) 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.
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 pharmacology
Sulfonylureas such as Madopar 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
The results of a survey conducted on ndrugs.com for Madopar are given in detail below. The results of the survey conducted are based on the impressions and views of the website users and consumers taking Madopar. We implore you to kindly base your medical condition or therapeutic choices on the result or test conducted by a physician or licensed medical practitioners.User reports
2 consumers reported administration
When best can I take Madopar, on an empty stomach, before or after food?ndrugs.com website users have also released a report stating that Madopar should be taken With a meal. In any case, this may not be the right description on how you ought to take this Madopar. Kindly visit your doctor for more medical advice in this regard. Click here to see other users view on when best the Madopar can be taken.
| Users | % | ||
|---|---|---|---|
| With a meal | 1 | 50.0% | |
| Before food | 1 | 50.0% | |
Consumer reviews
| Hola vivo en la Republica Argentina y tengo el mal de Parkinson y en mi pais no lo consigo mas. Me interesa comprale a Vds Madopar 250 por 1000 y desaria saber el costo puestro en Buenos Aires y forma de pago. A la esapera de su contestacion Saluda atte R:D.Garcia Colombo |
Information checked by Dr. Sachin Kumar, MD Pharmacology
