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Copyright Cleared Article
Pharmacology and pharmacokinetics
of rasagiline: A selective, irreversible,
second-generation MAO-B inhibitor
Jack J. Chen, PharmD, BCPS, CGP, FCPhA
Dr. Chen is Associate Professor (Neurology), School of
Pharmacy, and Clinical Associate Professor of Neurology,
School of Medicine and Movement Disorders Clinic, Loma
Linda University, Loma Linda, California.
The author would like to acknowledge Wallace J. Murray,
PhD, for assistance with chemical structure figures.
Rasagiline is a novel second-generation, irreversible,
selective monoamine oxidase type B (MAO-B) inhibitor
that differs chemically and pharmacologically from the
first-generation MAO-B inhibitor selegiline. Selegiline is
derived from an amphetamine pharmacophore and is
converted by cytochrome P450 to amphetamine metabolites that have been shown in vitro to be neurotoxic and,
clinically, may result in undesirable cardiovascular and
psychiatric side effects. Rasagiline has no intrinsic
amphetamine-like effects. Its major metabolite, aminoindan,
is not an amphetamine derivative, is devoid of neurotoxic
effects, and has also been shown to have beneficial
effects in animal models relevant to Parkinson disease
(PD). Rasagiline has been shown in preclinical studies to
enhance striatal levels of dopamine with or without
levodopa. Preclinical and clinical data indicate that
it is a more potent MAO-B inhibitor than selegiline.
with early disease, selegiline is considered clinically useful
as monotherapy for symptomatic control of PD.6 However,
the US Food and Drug Administration (FDA)-approved
labeling indicates selegiline only as adjunctive treatment
for PD in combination with levodopa/carbidopa. Despite
its wide clinical usage as adjunctive therapy, the clinical
evidence supporting this is modest.6
Rasagiline and selegiline are both aromatic N-propargylamines, but the compounds differ chemically and
pharmacologically in other ways. Selegiline is an
amphetamine (beta-phenylisopropylamine) derivative
and possesses indirect amphetamine-like sympathomimetic actions.7,8 Selegiline is converted by
cytochrome P450 (CYP450) isoenzymes to amphetamine
metabolites (Figure 1).9 N-dealkylation of selegiline by
CYP2B6 and CYP2C19 results in the formation of
L-methamphetamine and subsequently L-amphetamine.
Upon administration of conventional oral tablets,
selegiline undergoes extensive first-pass metabolism to
L-methamphetamine and L-amphetamine (Figure 1).9-11
L-amphetamine is detectable on drug testing12 and is similar to D-amphetamine in its sympathetic nervous system
activity.13 Consequently, selegiline-treated patients
may experience undesirable amphetamine-like side
effects (eg, insomnia and cardiac effects).14,15 Additionally,
the amphetamine metabolites have been shown to be
associated with neuronal toxicity.16,17
Rasagiline mesylate [N-propargyl-1(R)-aminoindan] is a novel, nonamphetamine, irreversible, and
selective inhibitor of monoamine oxidase type B
(MAO-B). It has been shown in phase 3 clinical trials to be an effective and safe once-daily monotherapy for patients with early Parkinson disease
(PD) and adjunctive therapy for patients with
advancing PD who have motor fluctuations
despite optimized levodopa therapy.1-4 The clinical
efficacy and safety of rasagiline are discussed in
detail elsewhere in this supplement.5
Historically, selegiline serves as the prototype firstgeneration, irreversible MAO-B selective inhibitor that
became available for the treatment of PD. In patients
Figure 1. Chemical structures and metabolic pathways for
selegiline (top)9 and rasagiline (bottom).
Rasagiline, a second-generation MAO-B inhibitor, was
designed specifically to be devoid of amphetamine-like
activity. Rasagiline is a nonamphetamine (phenylmethylamine) pharmacophore devoid of intrinsic sympathomimetic effects and amphetamine-like metabolites
(Figure 1). Two other nonamphetamine MAO-B selective
inhibitors, lazabemide and mofegiline, have been clinically evaluated for the treatment of PD, but have not
made it to market.18,19 Rasagiline is the first nonamphetamine, irreversible MAO-B selective inhibitor to become
available for treatment of PD. This article reviews its
mechanism of action and pharmacokinetics.
RATIONALE FOR MAO-B INHIBITION
IN PARKINSON DISEASE
PD is characterized by progressive degeneration of
melanin-containing dopaminergic neurons within the
substantia nigra pars compacta and profound depletion
of nigrostriatal dopamine. This state of dopamine deficiency within the basal ganglia results in dysequilibrium
of the extrapyramidal motor circuits and manifests as the
clinical syndrome of tremor, bradykinesia, rigidity, and
postural instability.20 Other neurotransmitters and
neuroanatomical nuclei are also adversely affected and
contribute to the motor and nonmotor features of PD.
The primary rationale for MAO-B inhibition in the
management of PD is enhancement of striatal
dopamine activity to produce symptomatic improvement of motor features. A secondary rationale is the
putative attenuation of neurodegeneration to lead to
increased neuronal survival and subsequent delayed
disease progression. Physiologically, the role of MAO is
to catalyze the oxidative deamination of a variety of
endogenous neurotransmitters, such as dopamine (DA),
epinephrine, norepinephrine, and serotonin, as well as
to detoxify exogenous monoamines, such as tyramine.
MAO-mediated breakdown of DA leads to production
of hydrogen peroxide and other reactive oxidative
products that may contribute to free radical-mediated
neurotoxicity, particularly in DA-rich nigrostriatal neurons.
The MAO enzyme is embedded in the outer membrane of
intracellular mitochondria. Two isoforms of MAO, types A
and B, have been described and differ with respect to
localization and substrate specificity (Table 1).21-23 The gastrointestinal and hepatic MAO-A isoform plays a crucial
role in deactivating circulating catecholamines and
dietary sympathomimetics (eg, tyramine), whereas brain
MAO-A contributes to oxidative deamination of DA, norepinephrine, and serotonin. Therapeutically, inhibition of
central MAO-A is useful for anxiety and depressive disorders, but it also has the potential for serious peripheral
and central pharmacodynamic MAO-A–mediated drug
interactions. Inhibition of MAO-A in the periphery can
lead to hypertensive crisis (“cheese effect”) when tyramine
and other agents (eg, amphetamine, epinephrine,
isometheptene, levodopa, and pseudoephedrine) are
ingested, while MAO-A inhibition in the central nervous
system is associated with a risk of serotonin syndrome
when selective serotonin reuptake inhibitors (SSRIs) or
other serotonin-enhancing agents are administered.
Table 1. Distribution and Activity of MAO-A and MAO-B in
Selected Human Tissues21-23
% Total MAO Activity
In the human brain, MAO-B is found in glial cells and is
the predominant isoform responsible for breakdown of
DA to inactive metabolites (ie, 3,4-dihydroxyphenylacetic acid and homovanillic acid [HVA]), as well as
for deamination of beta-phenylethylamine (PEA), an
endogenous amine that stimulates the release and inhibits
neuronal reuptake of DA. Therefore, selective inhibition of
central MAO-B is pharmacologically desirable for treating PD. Of note, brain MAO-B is also responsible for
conversion of the synthetic protoxin 1-methyl-4-phenyl1,2,3,6-tetrahydropyridine (MPTP) into the potent, parkinsonism-inducing neurotoxin, 1-methyl-4-phenylpyridinium
ion (MPP+).24 Inhibition of MAO-B attenuates MPTP neurotoxicity.25 Inhibition of platelet MAO-B is highly correlated with inhibition of brain MAO-B and thus serves as
a useful bioassay for clinical research.26
The administration of an irreversible and selective
inhibitor of MAO-B such as rasagiline results in a longlasting enhancement of striatal dopamine levels. This
augmentation of synaptic DA availability is derived
either from residual nigrostriatal neurons, exogenous levodopa, or increased synaptic concentrations of PEA.27-31
Based on this activity, rasagiline has proven symptomatic
benefits as monotherapy in early PD and is useful as an
adjunct in levodopa-treated patients for smoothing out
Rasagiline is a nonamphetamine, secondary cyclic
benzylamine propargylamine derivative.29 Rasagiline
binds covalently to form an irreversible bond with the
flavin adenine dinucleotide moiety of the MAO enzyme.32
Structure-activity relationship studies demonstrate that
the triple bond of the N-propargyl group (acetylenic) is
absolutely essential for irreversibility of MAO inhibition
and that maintaining a distance of no more than 2 carbon
units between the aromatic ring and the N-propargyl
terminal is essential for conferring selectivity for the MAO-B
isoform.33 As it turns out, the N-propargyl group is also
essential for neuroprotective effects that are independent
of MAO-B inhibition.34
In vitro and ex vivo animal studies conducted to characterize and compare the activity of the R(+) and S(-)
optical isomers of N-propargyl-1-aminoindan showed
that the (S)-isomer (TVP-1022) was a very weak MAO
inhibitor, whereas the (R)-isomer (TVP-1012) was a
potent and preferential inhibitor of MAO-B. In vitro, the
(R)-isomer inhibits MAO-B 30 to 100 times more
potently than MAO-A (based on IC50 [nmol/L] values).
Ex vivo, the (R)-isomer is 17 to 65 times more potent at
inhibiting MAO-B over MAO-A (based on ED50 [mg/kg]
values).35,36 The variability in these results reflects differences in experimental conditions and techniques,
but the data demonstrate the relative potency of the
(R)-isomer for MAO-B inhibition. Subsequently, the
(R)-isomer, N-propargyl-1(R)-aminoindan, was assigned
the official generic name rasagiline and advanced into
Rasagiline is rapidly absorbed by the gastrointestinal
tract and readily crosses the blood-brain barrier.36,37 The
bioavailability of rasagiline is approximately 36%.38 The
bioavailability of oral rasagiline is slightly affected by
concomitant ingestion of food. Relative to values measured when rasagiline was ingested in the fasting state,
maximum plasma concentration (Cmax) was decreased by
approximately 60% and area under the concentrationtime curve (AUC) was reduced by approximately 20%
when rasagiline was administered with a high-fat meal.38
These changes are considered clinically insignificant
(since AUC is not substantially affected) and rasagiline
may be administered with or without food.38
Rasagiline is widely distributed into tissues as indicated
by a mean volume of distribution (Vd) of approximately
87 L. Plasma protein binding ranges from 88% to 94%
with mean extent of binding of 61% to 63% to human
albumin over the concentration range of 1 to 100 ng/mL.38
Rasagiline exhibits dose linearity and proportionality
for Cmax and AUC values over the dose range of 0.5 to 2 mg.
Selected pharmacokinetic parameters obtained from
multiple-dose studies of orally administered rasagiline
in healthy subjects and in patients with PD are listed in
Table 2.39,40 In patients with PD treated once daily with
rasagiline for 12 weeks, the mean Cmax observed was 8.5
ng/mL with 1 mg and 14.9 ng/mL with 2 mg40,41; the time
to reach those concentrations (Tmax) ranged from 0.5 to
0.7 hours.39 Consistent with the results in PD patients,
mean Cmax reached 17.6 ng/mL and mean Tmax was about
0.4 hours in a multidose study where young, healthy men
received rasagiline 2 mg.40 The mean steady-state halflife (t1/2) of rasagiline in patients with PD and healthy
subjects is 3 hours.38-40 However, since rasagiline is an
irreversible MAO-B inhibitor, the plasma t1/2 does not correlate with duration of symptomatic effect. Rather,
restoration of normal MAO-B activity depends on the de
novo rate of enzyme synthesis. Studies in humans indicate that the recovery t1/2 of brain MAO-B after irreversible inhibition (by selegiline) is 40 days.42 In patients
with PD treated with rasagiline for 12 weeks, the clinical
effects of rasagiline were measurable for up to 6 weeks
after drug discontinuation.39 In a multiple-dose study
where rasagiline 2, 5, or 10 mg was administered once
daily for 10 days, platelet MAO-B was significantly
inhibited at least 1 week after the last dose.40
Table 2. Pharmacokinetics of Rasagiline and the Major Metabolite, Aminoindan, in Young, Healthy Men* and in
Patients With Parkinson Disease39,40
Values expressed as mean (standard deviation)
Cmax = maximum plasma concentration; AUC = area under the concentration-time curve; Tmax = time to maximum plasma concentration; t1/2 = terminal half-life; nr = not reported.
*After daily dosing for 10 days.
After daily dosing for 12 weeks (84 days).
Tmax of 0.5 to 0.7 hours reported for 0.5-, 1-, and 2-mg doses.
Rasagiline undergoes CYP450 1A2-mediated N-dealkylation to form aminoindan, a major metabolite that has no
amphetamine-like properties13,35,43 or MAO-inhibitory activity, but was associated with modest improvements in
motor and cognitive function in animal models.44
Rasagiline also undergoes CYP450-mediated hydroxylation
to 3-hydroxy-N-propargyl-1-aminoindan and 3-hydroxy1-aminoindan. Rasagiline metabolites are predominantly
excreted in the urine; less than 1% of the parent drug is
excreted as unchanged drug in the urine. Because renal
impairment does not significantly affect rasagiline AUC,
dose adjustment for renal insufficiency is not required. The
AUC of rasagiline increases almost 2-fold in patients with
mild hepatic impairment and by almost 7-fold in patients
with moderate hepatic impairment.38 Rasagiline should be
used with caution at a reduced dose in patients with mild
hepatic impairment and should not be used in those with
more severe liver dysfunction.38
Gender does not influence the pharmacokinetic parameters of rasagiline.38 Overall, age has minimal influence on
rasagiline pharmacokinetics, and the drug can be administered without dose adjustment in the elderly.38 Two post
hoc analyses of pooled data from large clinical trials suggest an absence of age-related differences in efficacy and
show rasagiline is well tolerated in the elderly (>65 to
70 years old), although there was a higher rate of hallucinations among older patients treated with rasagiline in
combination with levodopa.45,46 Based on these data, any
age-related pharmacokinetic alterations are anticipated
to be clinically insignificant.4
Rasagiline does not interact with alpha-adrenoreceptors,
beta-adrenoreceptors, or muscarinic receptors.31 The ability
of rasagiline to potently and completely inhibit MAO-B
activity has been established by several in vitro and in vivo
animal studies as well as studies in healthy human volunteers and patients with PD. The ability of rasagiline to
increase basal synaptosomal levels of DA in the striatum,
with or without levodopa pretreatment, has also been
established in several preclinical studies that used microdialysis techniques.27-30 In these models, the enhanced
synaptic availability of DA was shown to be a function of
reduced breakdown of DA derived from residual nigrostriatal
neurons and from exogenous levodopa administration, as
well as from increased DA secretion due to elevated synaptic concentrations of PEA, an endogenous amine that stimulates release and inhibits neuronal reuptake of DA.
Overall, these findings are consistent with clinical results
demonstrating that rasagiline provides symptomatic benefits when used as monotherapy in patients with PD and,
when given as an adjunctive agent, improves both PD
symptoms and motor fluctuations.
MAO-B inhibition: Human data. In a single-dose investigation, young, healthy men were administered rasagiline 1 to
20 mg orally.40 All doses were well tolerated. Inhibition
of platelet MAO-B activity was achieved rapidly, indicating rapid cellular uptake, and exhibited a dosedependent effect. Platelet MAO-B inhibition within 1 hour
after administration of rasagiline 1, 2, 5, and 10 mg
was approximately 35%, 55%, 79%, and 99%, respectively. Approximately 85% inhibition of MAO-B is
required for pharmacologic effects and is considered
In another study, rasagiline 2, 5, and 10 mg was administered once daily for 10 consecutive days to young, healthy
men.40 Platelet MAO-B activity was significantly inhibited
soon after the first oral dose and was maintained with
repeated dosing (Figure 2).40 All doses were administered
without food and were well tolerated during the study
period. After the last dose, inhibition of platelet MAO-B
activity remained significant for 7 days and returned to
baseline after 2 weeks. Near-complete (>90%) inhibition of
MAO-B activity was achieved at all doses, with higher
doses achieving this end point more rapidly. Rasagiline
dose was not correlated with changes in urinary concentrations of DA, HVA, or 5-hydroxyindoleacetic acid, and
serotonin was not detected in the urine after chronic rasagiline administration.40 Similar results were obtained from
patients with PD in which repeated daily oral administration of rasagiline 0.5 mg or higher for 1 week resulted in
near-complete inhibition of platelet MAO-B activity after
the third daily dose.39 These results suggest that once-daily
administration of rasagiline is sufficient to provide pharmacologically significant and selective MAO-B inhibition.
Reproduced with permission from Pharmcotherapy. 2004;24:1301.
Figure 2. Percentage inhibition of platelet MAO-B following repeated oral administration of rasagiline for 10 days
in young, healthy, adult men.40
Studies suggest that concentrations of brain MAO-B
increase with age, perhaps because of age-associated
increases in glial cells.48 However, in patients with PD, the
clinical effects of rasagiline are not affected by age.4,45
MAO-B inhibition: Potency versus selegiline. Rasagiline
mesylate has a molecular weight of 267.34, which is similar to that of selegiline hydrochloride, 223.75. In vitro
human brain homogenate experiments indicate that
selegiline is twice as potent as rasagiline on a molecular
basis.36 Data from ex vivo rat brain experiments,
however, suggest that rasagiline is 5 to 10 times more
potent for MAO-B inhibition compared with selegiline,
based on dose (ED50).29,36 Additionally, investigators have
reported that rasagiline is 5 times more potent than
selegiline in vivo as measured by effects on platelet
MAO-B inhibition.36 However, ED50 and IC50 values reflect
50% inhibition of enzyme activity. Based on the dose of
rasagiline required to achieve a clinically relevant
degree of MAO-B inhibition (>80%), rasagiline is 10 times
more potent compared with selegiline.36
MAO-B inhibition: Selectivity versus selegiline. In vitro experiments with rat brain homogenate suggest that rasagiline is 30 to 65 times more selective for MAO-B over
MAO-A.29,35 Ex vivo experiments in rat brains demonstrate that rasagiline is 17 to 65 times more selective for
MAO-B29,35,36 and, in vitro, rasagiline is 50 times more
selective for MAO-B in human brain homogenate studies.36
Thus, various in vitro and ex vivo experiments have established that rasagiline is highly selective for MAO-B.35,36 In
ex vivo rat intestinal and liver tissue experiments, rasagiline is a weak inhibitor of MAO-A across a wide dose range
(pharmacologically active), suggesting that it is associated
with a low risk of peripheral tyramine potentiation.36
Drug interactions with rasagiline can be divided into pharmacodynamic and pharmacokinetic interactions. In the category of pharmacodynamic interactions, rasagiline would
be expected to augment the activity of exogenously administered levodopa/carbidopa and to permit reduction of levodopa/carbidopa dose. Results from a phase 3 clinical trial
showed that the addition of rasagiline in patients receiving
levodopa with or without concomitant drugs (dopamine
agonists, entacapone) was associated with significant
improvement in PD symptoms and in motor fluctuations.
There was a modest 24-mg reduction in total mean daily
levodopa dose at the end of the 18-week study period (levodopa dosage adjustment was allowed only in the first 6
weeks of the study).4 A post hoc analysis has shown similar efficacy and safety when rasagiline was administered to
patients taking levodopa with or without concomitant
dopamine agonist or entacapone therapy.49
Tyramine and sympathomimetic potentiation. At recom-
mended doses, rasagiline selectively inhibits MAO-B.
Therefore, interference with MAO-A–mediated metabolism
of concomitantly ingested tyramine or other indirectly
acting sympathomimetics associated with the cheese
effect is not anticipated. Although a tyramine reaction is
unlikely at standard doses of rasagiline, the FDA has recommended that patients taking rasagiline avoid foods
high in tyramine.
The potential for a rasagiline-tyramine interaction has
been investigated in clinical trials. In a phase 3 trial investigating rasagiline 1 and 2 mg as monotherapy in patients
with early PD, a subset of patients received an oral challenge of tyramine 75 mg on the last day of the 26-week
study.50 Blood pressure was not significantly affected.
Other tyramine challenge studies have been conducted in
healthy volunteers and PD patients treated with rasagiline alone or with chronic levodopa therapy, and daily
home blood pressure monitoring was performed by
subjects receiving placebo or rasagiline 0.5 or 1 mg/d as
adjunct therapy to levodopa for 6 months.51 Based on the
absence of significant interactions in those studies,
rasagiline at recommended doses is not expected to
induce the cheese effect. MAO-A inhibition may be
expected to occur with administration of higher-thanrecommended doses of rasagiline, however.
The pharmacodynamic effect (ie, hypertensive crisis)
resulting from concomitant administration of sympathomimetic agents (eg, amphetamines, ephedrine, epinephrine, isometheptene, pseudoephedrine) with rasagiline is
unknown. Some of these sympathomimetic agents are
available in over-the-counter products. In the clinical
studies of rasagiline, sympathomimetic use was prohibited,
but based on wide clinical experience with selegiline, the
risk of hypertensive crisis associated with occasional
administration of over-the-counter sympathomimetic
agents (eg, pseudoephedrine) appears to be minimal.52
Serotonin syndrome. As with selegiline and nonselective
MAO inhibitors (eg, phenelzine, tranylcypromine), the
concurrent use of meperidine and rasagiline is
contraindicated because of the potential for serotonin
syndrome. Theoretically, pharmacodynamic potentiation
between rasagiline and serotonergic agents (eg, SSRIs)
may result in the serotonin syndrome. Concomitant use
of limited doses of some antidepressants (ie, amitriptyline
50 mg/d, trazodone ≤100 mg/d, sertraline ≤100 mg/d,
citalopram ≤20 mg/d, and paroxetine ≤30 mg/d) was
allowed in phase 3 clinical trials of rasagiline and no
reports of the serotonin syndrome were noted in patients
treated with rasagiline.1,2,4 Concomitant use of fluoxetine
and fluvoxamine was not studied.
Pharmacokinetic interactions. In vitro studies indicate that
rasagiline does not inhibit the CYP450 enzyme system.38
Concurrent administration of CYP450 1A2 inducers
(eg, omeprazole) or inhibitors (eg, cimetidine, ciprofloxacin)
may alter plasma levels of rasagiline, however.
Ciprofloxacin 500 mg bid increased rasagiline AUC by
approximately 83% in healthy subjects treated with
rasagiline 2 mg/d but did not alter the t1/2 of rasagiline; its
use is contraindicated with rasagiline.38
Concurrent administration of drugs that displace
rasagiline bound to plasma proteins may increase the
concentration of unbound rasagiline. However, since
rasagiline has demonstrated a wide therapeutic index,
clinically significant protein displacement interactions
are not anticipated.
Since the introduction of levodopa in the late 1960s,
many significant advances have occurred in the pharmacologic treatment of PD.20 Despite numerous agents
available for symptomatic treatment of PD, the search
for neuroprotective agents to prevent or slow neuronal
death and slow disease progression remains the focus
of PD research. Rasagiline is one of several compounds recently identified by the National Institute of
Neurological Disorders and Stroke as a potential neuroprotective agent that merits further clinical investigation in PD.53 The neuroprotective properties of
rasagiline are discussed in detail elsewhere within this
supplement,54 but are summarized here.
In both in vitro and in vivo experiments, rasagiline has
demonstrated neuroprotective activity against a variety of
PD-relevant toxins, including glutamate, 6-hydroxydopamine, MPTP, MPP+, and N-methyl(R)salsolinol.31,55-58
Experiments also suggest that the neuroprotective or neurorestorative properties of rasagiline may be more potent
than selegiline.17,29,54,58,59 The major metabolite of rasagiline,
aminoindan, is not neurotoxic and does not interfere with
the neuroprotective activity of rasagiline.17 In fact,
aminoindan (which is not a MAO inhibitor) has also
demonstrated neuroprotective properties.59 In contrast,
L-methamphetamine, a major metabolite of selegiline,
was found to be neurotoxic and to block the neuroprotective activity of selegiline in experimental systems.17,59
In vitro experiments do not support a direct free-radical scavenging mechanism associated with the neuroprotective effects of rasagiline.60 Rather, its benefit
appears to be mediated through an effect that is independent of its MAO-B inhibition.29,55,56,59,61 In addition to
conferring irreversibility of MAO-B inhibition, the
N-propargyl moiety of propargylamines (eg, rasagiline
and selegiline) is essential for conferring neuroprotective activity.34 As discussed elsewhere in this supplement, the 1-year, phase 3, double-blind, randomized,
parallel-group, TVP-1012 in Early Monotherapy for
Parkinson’s disease Outpatients (TEMPO) delayed-start
trial suggests that rasagiline may be associated with
clinically meaningful disease modification (ie, slow the
progression of functional impairments in PD).3
Rasagiline has also demonstrated neuroprotection in a
variety of non–PD- and PD-related models, such as the
6-hydroxydopamine model,62 beta-amyloid toxicity,63
experimental ischemia,64,65 nonpenetrating closed head
injury,66 salt-loaded stroke-prone hypertensive rats,67 and
spontaneously hypertensive rats.68 These findings suggest
that rasagiline may have disease-modifying activity in
PD and other neurodegenerative diseases.
Rasagiline is the first nonamphetamine, irreversible,
MAO-B selective inhibitor available for the treatment of
PD. Rasagiline enhances striatal dopamine activity with
or without levodopa and exhibits a pharmacokinetic profile suitable for once-daily administration. The N-propargylamine moiety confers rasagiline with potent MAO-B
inhibition as well as neuroprotective effects that are independent of its MAO-B inhibitory activity. Experiments
demonstrate that rasagiline has more potent MAO-B
inhibitory and neuroprotective properties compared with
selegiline, the first-generation amphetamine-derived
MAO-B selective inhibitor. Rasagiline metabolism is predominantly mediated by CYP450 1A2, and its major
metabolite, aminoindan, does not possess neurotoxic or
sympathomimetic activity. Based on pharmacodynamic
and pharmacokinetic properties, rasagiline would be
expected to provide symptomatic benefits within a wide
therapeutic index in patients with early and moderateto-advanced PD. Experimental data also suggest that
rasagiline may offer putative neuroprotective effects.
Results from a phase 3 registration study have provided
preliminary clinical data to suggest that rasagiline
may have a positive disease-modifying effect and
additional studies to verify this effect are under way.
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