Chemical formula: C₁₂H₁₃N Molecular mass: 171.238 g/mol PubChem compound: 3052776
Rasagiline was shown to be a potent, irreversible MAO-B selective inhibitor, which may cause an increase in extracellular levels of dopamine in the striatum. The elevated dopamine level and subsequent increased dopaminergic activity are likely to mediate rasagiline’s beneficial effects seen in models of dopaminergic motor dysfunction.
1-Aminoindan is an active major metabolite and it is not a MAO-B inhibitor.
Rasagiline is rapidly absorbed, reaching peak plasma concentration (Cmax) in approximately 0.5 hours. The absolute bioavailability of a single rasagiline dose is about 36%.
Food does not affect the Tmax of rasagiline, although Cmax and exposure (AUC) are decreased by approximately 60% and 20%, respectively, when the medicinal product is taken with a high fat meal.
Because AUC is not substantially affected, rasagiline can be administered with or without food.
The mean volume of distribution following a single intravenous dose of rasagiline is 243 l.
Plasma protein binding following a single oral dose of 14C-labelled rasagiline is approximately 60 to 70%.
Rasagiline undergoes almost complete biotransformation in the liver prior to excretion. The metabolism of rasagiline proceeds through two main pathways: N-dealkylation and/or hydroxylation to yield: 1-aminoindan, 3-hydroxy-N-propargyl-1 aminoindan and 3-hydroxy-1-aminoindan. In vitro experiments indicate that both routes of rasagiline metabolism are dependent on cytochrome P450 system, with CYP1A2 being the major iso-enzyme involved in rasagiline metabolism. Conjugation of rasagiline and its metabolites was also found to be a major elimination pathway to yield glucuronides. Ex vivo and in vitro experiments demonstrate that rasagiline is neither inhibitor nor inducer of major CYP450 enzymes.
After oral administration of 14C-labelled rasagiline, elimination occurred primarily via urine (62.6%) and secondarily via faeces (21.8%), with a total recovery of 84.4% of the dose over a period of 38 days. Less than 1% of rasagiline is excreted as unchanged product in urine.
Rasagiline pharmacokinetics is linear with dose over the range of 0.5-2 mg in Parkinson’s disease patients. Its terminal half-life is 0.6-2 hours.
In subjects with mild hepatic impairment, AUC and Cmax were increased by 80% and 38%, respectively. In subjects with moderate hepatic impairment, AUC and Cmax were increased by 568% and 83%, respectively.
Rasagiline’s pharmacokinetics characteristics in subjects with mild (CLcr 50-80 ml/min) and moderate (CLcr 30-49 ml/min) renal impairment were similar to healthy subjects.
Age has little influence on rasagiline pharmacokinetics in the elderly (>65 years).
Non-clinical data reveal no special hazard for humans based on the standard studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenicity, reproduction and development.
Rasagiline did not present genotoxic potential in vivo and in several in vitro systems using bacteria or hepatocytes. In the presence of metabolite activation rasagiline induced an increase of chromosomal aberrations at concentrations with excessive cytotoxicity which are unattainable at the clinical conditions of use.
Rasagiline was not carcinogenic in rats at systemic exposure, 84-339 times the expected plasma exposures in humans at 1 mg/day. In mice, increased incidences of combined bronchiolar/alveolar adenoma and/or carcinoma were observed at systemic exposures, 144-213 times the expected plasma exposure in humans at 1 mg/day.
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