Pharmacodynamics Monoamine oxidase inhibitor Parkinson's disease is characterized by the death of cells that produce
dopamine, a
neurotransmitter. An enzyme called
monoamine oxidase (MAO) breaks down neurotransmitters. MAO has two forms,
MAO-A and
MAO-B. MAO-B is involved in the metabolism of
dopamine. Rasagiline prevents the breakdown of dopamine by irreversibly binding to MAO-B. Dopamine is therefore more available, somewhat compensating for the diminished quantities made in the brains of people with Parkinson's disease. With all dose levels, maximum inhibition is maintained for at least 48hours after the dose. The clinical effectiveness of rasagiline in Parkinson's disease has been found to persist during a 6-week washout phase with discontinuation of the medication. Selegiline and rasagiline have similar
selectivity for inhibition of MAO-B over MAO-A. These metabolites
induce the release of norepinephrine and dopamine, have
sympathomimetic and
psychostimulant effects, and may contribute to the effects and
side effects of selegiline. In contrast to selegiline, rasagiline does not convert into
metabolites with amphetamine-like effects. The amphetamine metabolites of selegiline may contribute to significant clinical differences between selegiline and rasagiline. It has been theorized that this might be due to strong inhibition of the metabolism of
β-phenylethylamine, which is an
endogenous MAO-B substrate that has
monoaminergic activity enhancer and
norepinephrine–dopamine releasing agent actions. β-Phenylethylamine has been described as "endogenous amphetamine" and its brain levels are dramatically increased (10- to 30-fold) by MAO-B inhibitors like selegiline. In contrast, MAO-B appears to mediate
tonic γ-aminobutyric acid (GABA) synthesis from
putrescine in the striatum, a minor and alternative
metabolic pathway of GABA synthesis, and this synthesized GABA in turn inhibits dopaminergic neurons in this brain area. MAO-B specifically mediates the
transformations of putrescine into
γ-aminobutyraldehyde (GABAL or GABA aldehyde) and
N-acetylputrescine into
N-acetyl-γ-aminobutyraldehyde (
N-acetyl-GABAL or
N-acetyl-GABA aldehyde),
metabolic products that can then be converted into GABA via
aldehyde dehydrogenase (ALDH) (and an unknown
deacetylase enzyme in the case of
N-acetyl-GABAL). The major metabolite of rasagiline,
(R)-1-aminoindan, is either devoid of MAO inhibition or shows only weak inhibition of MAO-B. It also has no
amphetamine-like activity. 1-Aminoindan has been found to inhibit the reuptake of norepinephrine 28-fold less potently than 2-aminoindan and to inhibit the reuptake of dopamine 300-fold less potently than 2-aminoindan, with values for dopamine reuptake inhibition in one study of 0.4μM for
amphetamine, 3.3μM for 2-aminoindan, and 1mM for 1-aminoindan. In contrast to 2-aminoindan, which
increased locomotor activity in rodents (+49%), 1-aminoindan
suppressed locomotor activity (–69%). Instead, rasagiline actually antagonizes selegiline's effects as a catecholaminergic activity enhancer, which may be mediated by TAAR1
antagonism. Rasagiline has been reported to directly bind to and
inhibit glyceraldehyde-3-phosphate dehydrogenase (GAPDH). This might play a modulating role in its clinical effectiveness for Parkinson's disease.
Pharmacokinetics Absorption Rasagiline is rapidly
absorbed from the
gastrointestinal tract with
oral administration and has approximately 36%
absolute bioavailability. It is also metabolized by
hydroxylation via cytochrome P450 enzymes to form 3-hydroxy-
N-propargyl-1-aminoindan (3-OH-PAI) and 3-hydroxy-1-aminoindan (3-OH-AI). Variants in CYP1A2 have been found to modify exposure to rasagiline in some studies but not others.
Tobacco smoking, a known inhibitor of CYP1A2, did not modify rasagiline exposure.
Drug transporters may be more important in influencing the pharmacokinetics of rasagiline than metabolizing enzymes. Exposure to rasagiline is increased in people with
hepatic impairment. In those with mild hepatic impairment, peak levels of rasagiline are increased by 38% and area-under-the-curve levels by 80%, whereas in people with moderate hepatic impairment, peak levels are increased by 83% and area-under-the-curve levels by 568%. As a result, the dosage of rasagiline should be halved to 0.5mg/day in people with mild hepatic impairment and rasagiline is considered to be
contraindicated in people with moderate to severe hepatic impairment.
Elimination Rasagiline is
eliminated primarily in
urine (62%) and to a much lesser extent in
feces (7%). Rasagiline is
excreted unchanged in urine at an amount of less than 1%. Hence, it is almost completely metabolized prior to excretion. The
elimination half-life of rasagiline is 1.34hours. At
steady-state, its half-life is 3hours. As rasagiline acts as an
irreversible inhibitor of MAO-B, its actions and
duration of effect are not dependent on its half-life or sustained concentrations in the body. The oral
clearance of rasagiline is 94.3L/h and is similar to normal liver blood flow (90L/h). This indicates that non-hepatic mechanisms are not significantly involved in the elimination of rasagiline. Moderate
renal impairment did not modify exposure to rasagiline, whereas that of
(R)-1-aminoindan was increased by 1.5-fold. Since (
R)-1-aminoindan is not an MAO inhibitor, mild to moderate renal impairment does not require dosage adjustment of rasagiline. No data are available in the case of severe or end-stage renal impairment. ==Chemistry==