A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Eldepryl Pharmacology, Pharmacokinetics, Studies, Metabolism - Selegiline
Eldepryl Pharmacology, Pharmacokinetics, Studies, Metabolism - Selegiline
CLINICAL PHARMACOLOGY
The mechanisms accounting for selegiline's beneficial adjunctive
action in the treatment
of Parkinson's disease
are not fully understood. Inhibition of monoamine
oxidase, type B, activity
is generally considered to be of primary importance; in addition,
there is evidence that
selegiline may act through other mechanisms to increase dopaminergic
activity.
Selegiline is best known as an irreversible
inhibitor of monoamine
oxidase (MAO), an intracellular
enzyme associated with
the outer membrane
of mitochondria. Selegiline inhibits MAO
by acting as a 'suicide' substrate
for the enzyme; that is, it is converted by MAO
to an active moiety which
combines irreversibly with the active site
and/or the enzyme's essential
FAD cofactor. Because selegiline
has greater affinity
for type B than for type
A active sites, it can serve as a selective inhibitor
of MAO type
B if it is administered at the recommended dose.
MAOs are widely distributed throughout the body; their concentration
is especially high in liver,
kidney, stomach,
intestinal wall,
and brain. MAOs are currently subclassified into two types, A and
B, which differ in their substrate
specificity and
tissue distribution.
In humans, intestinal MAO
is predominantly type A,
while most of that in brain
is type B.
In CNS neurons, MAO
plays an important role
in the catabolism
of catecholamines (dopamine, norepinephrine
and epinephrine) and serotonin. M.O.
are also important in the catabolism
of various exogenous
amines found in a variety of foods and drugs. MAO
in the GI tract
and liver (primarily type
A), for example, is thought to provide vital
protection from exogenous
amines (e.g., tyramine) that have the capacity, if absorbed
intact, to cause a 'hypertensive
crisis,' the so-called 'cheese reaction.' (If large amounts of certain
exogenous amines gain access
to the systemic circulation
[e.g., from fermented cheese, red
wine, herring, over-the-counter cough/cold medications, etc.] they
are taken up by adrenergic
neurons and displace norepinephrine
from storage sites within membrane
bound vesicles. Subsequent
release of the displaced
norepinephrine
causes the rise in systemic
blood pressure,
etc.)
In theory, therefore, because MAO
A of the gut is not inhibited,
patients treated with selegiline at a dose
of 10 mg a day can take
medications containing pharmacologically active amines and consume
tyramine-containing foods without risk of uncontrolled hypertension.
However, one case of hypertensive
crisis has been reported in a patient
taking the recommended dose
of selegiline and a sympathomimetic
medication (ephedrine).
The pathophysiology
of the 'cheese reaction' is complicated and
in addition to its
ability to inhibit MAO
B selectively, selegiline's relative freedom from this reaction
has been attributed to an ability
to prevent tyramine
and other indirect acting sympathomimetrics from displacing norepinephrine
from adrenergic neurons.
However, until the pathophysiology
of the c.e.s. reaction
is more completely understood, it seems prudent to assume that selegiline
can only be used safely without dietary
restrictions at doses where it presumably selectively inhibits MAO
B (e.g., 10 mg/day). In short, attention
to the dose dependent nature of selegiline's selectivity is critical
if it is to be used without elaborate restrictions being placed
on diet and concomitant
drug use although, as noted above, a case
of hypertensive
crisis has been reported
at the recommended dose. (See WARNINGS
and PRECAUTIONS.)
It is important to be aware that selegiline may have pharmacological
effects unrelated to MAO
B inhibition. As noted above,
there is some evidence that it may increase dopaminergic
activity by other mechanisms,
including interfering with dopamine re-uptake at the synapse. Effects
resulting from selegiline administration
may also be mediated through its metabolites. Two of its three principal
metabolites, amphetamine
and methamphetamine, have pharmacological actions of their o.n.
they interfere with neuronal uptake and enhance release
of several neurotransmitters (e.g., norepinephrine, dopamine,
serotonin). However, the extent to which these metabolites contribute
to the effects of selegiline are unknown.
Rationale for the Use of a Selective Monoamine Oxidase Type
B Inhibitor in Parkinson's Disease: Many of the prominent symptoms
of Parkinson's disease are due to a deficiency
of striatal dopamine
that is the consequence of a progressive
degeneration and
loss of a population
of dopaminergic neurons which originate in the substantia
nigra of the midbrain
and project to the basal
ganglia or striatum.
Early in the course of Parkinson's, the deficit in the capacity
of these neurons to synthesize
dopamine can be overcome by administration
of exogenous levodopa,
usually given in combination with a peripheral
decarboxylase
inhibitor (carbidopa).
With the passage of
time, due to the progression
of the disease and/or
the effect of sustained
treatment, the efficacy
and quality of the therapeutic
response to levodopa
diminishes. Thus, after several years of levodopa treatment, the
response, for a given dose
of levodopa, is shorter, has less predictable onset and offset (i.e.,
there is "wearing off"), and is often accompanied by side
effects (e.g., dyskinesia, akinesias, on-off phenomena, freezing,
etc.).
This deteriorating response
is currently interpreted as a manifestation of the inability of
the ever decreasing population
of intact nigrostriatal neurons to synthesize
and release adequate
amounts of dopamine.
MAO B inhibition
may be useful in this setting because, by blocking the catabolism
of dopamine, it would increase the net amount of dopamine available
(i.e., it would increase the p.o.
of dopamine). Whether or not this mechanism
or an alternative one actually accounts for the observed beneficial
effects of adjunctive selegiline is unknown.
Selegiline's benefit
in Parkinson's disease
has only been documented as an adjunct
to levodopa/carbidopa. Whether or not it might be effective as a
sole treatment
is unknown, but past attempts to treat Parkinson's disease with
non-selective M.O. monotherapy
are reported to have been unsuccessful. It is important to note
that attempts to treat Parkinsonian patients with combinations of
levodopa and currently
marketed non-selective MAO
inhibitors were abandoned because of multiple
side effects including
hypertension, increase in involuntary
movement, and toxic delirium.
Pharmacokinetic Information (Absorption, Distribution, Metabolism
and Elimination--ADME): Only preliminary information about the
details of the pharmacokinetics
of selegiline and its metabolites is available.
Data obtained in a study of 12 healthy
subjects that was intended to examine the effects of selegiline
on the ADME of an oral
hypoglycemic agent, however, provides some information. Following
the oral administration
of a single dose of 10
mg of selegiline hydrochloride
to these subjects, serum levels of intact selegiline were below
the limit of detection
(less than 10 ng/ml). Three metabolites, N-desmethyldeprenyl, the
major metabolite (mean half-life
2.0 hours), amphetamine
(mean half- life 17.7 hours),
and methamphetamine (mean half-life
20.5 hours), were found in serum
and urine. Over a period
of 48 hours, 45% of the dose
administered appeared in the urine as these 3 metabolites.
In an extension of
this study intended to examine the effects of steady state conditions,
the same subjects were given a 10 mg
dose of selegiline hydrochloride
for seven consecutive days. Under these conditions, the mean trough
serum levels for amphetamine
were 3.5 ng/ml and 8.0 ng/ml for methamphetamine; trough levels
of N-desmethyldeprenyl were below the levels of detection.
The rate of MAO
B regeneration
following discontinuation of treatment has not been quantitated.
It is this rate, dependent upon de novo protein synthesis,
which seems likely to determine how fast
normal MAO B activity
can be restored.
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