REVIEW
Levodopa Therapy for Parkinson’s Disease: Pharmacokinetics and
Pharmacodynamics
Peter A. LeWitt, MD, MMedSc*
Parkinson’s Disease and Movement Disorders Center, Henry Ford Hospital, West Bloomfield, Michigan; and the Department of Neurology,
Wayne State University School of Medicine, Detroit, Michigan, USA
ABSTRACT: For all its imperfections at treating
Parkinson’s disease (PD), orally-administered levodopa
(L-dopa) can be regarded as the “platinum” standard of
PD therapeutics for its impact on disability and discom-
fort and its cost-effectiveness. The past half-century has
confirmed that the typical L-dopa–treated patient gains
improvement for most Parkinsonian features, presumably
by conversion of this amino acid into dopamine in the
striatum. However, fundamental questions remain as to
its full mechanism of action and how adverse reactions
evolve. Various aspects of clinical phenomenology asso-
ciated with chronic L-dopa use (such as dyskinesias and
the long-duration anti-Parkinsonian response) present a
Neither obsolete nor ideal as a medication, levo-3,4-
dihydroxy-phenylalanine (levodopa [L-dopa]) is now
celebrating a half-century of service to Parkinson’s dis-
ease (PD) patients. It also faces an ongoing challenge
to re-invigorate itself by new formulations improving
on dose-by-dose motor fluctuations and other thera-
peutic limitations. After L-dopa’s arrival into the ther-
apeutic arena,1,2 which followed several years of false
starts, this amino acid radically transformed the image
of PD away from a disorder of inevitable discomfort
and disability. Today, most patients with PD achieve
------------------------------------------------------------
*Correspondence to: Peter A. LeWitt, MD, MMedSc, Parkinson’s Dis-
ease and Movement Disorders Center, Henry Ford Hospital—West
Bloomfield, 6777 West Maple Road, West Bloomfield, MI 48322 USA,
E-mail: plewitt1@hfhs.org
Funding agencies: This study was supported by a gift from MAC Valves
Foundation.
Relevant conflicts of interest/financial disclosures: Nothing to report.
Full financial disclosures and author roles may be found in the online ver-
sion of this article.
Received: 23 September 2014; Revised: 9 October 2014; Accepted:
16 October 2014
Published online 00 Month 2014 in Wiley Online Library
(wileyonlinelibrary.com). DOI: 10.1002/mds.26082
continuing challenge for better understanding of its
pharmacology. The pharmacokinetics of L-dopa tend to
predict some of problems that can emerge during chronic
therapy, which can be linked with its irregular uptake and
marked dose-by-dose variability in plasma concentra-
tions. Several new pharmaceutical approaches are tar-
geted at the unique physiology of L-dopa uptake and are
likely to improve the consistency of its anti-Parkinsonian
effect. VC 2014 International Parkinson and Movement
Disorder Society
K e y W o r d s : levodopa; carbidopa; pharmacoki-
netics; pharmacodynamics; Parkinson’s disease
long-term benefit with the regular use of L-dopa. Past
concerns about toxicity or other considerations for
avoiding L-dopa have been largely put to rest.3 L-dopa
is commonly regarded as the “gold standard” of PD
therapy (but probably deserves an upgrade to
“platinum”!), reflecting its therapeutic superiority to
all other anti-Parkinsonian treatments (including drugs
more potent in dopaminergic properties). Given its
overall impact on disability, quality of life, and lon-
gevity, L-dopa stands out as one of the most cost-
effective medications ever to have been developed.
Patients averse to medication can also take some com-
fort in knowing that L-dopa is a “natural” substance,
found as a normal intermediate in human metabolism
and present in some foods.
L-dopa’s potential for treating Parkinsonism became
known by the rapid reversal of hypokinesia it accom-
plished in the reserpinized rabbit.4 With this information,
a strategy for enhancing striatal dopaminergic neuro-
transmission became an obvious priority.5 This goal
could not be achieved by dopamine, because this mole-
cule’s electrical charge prevents its movement across the
blood–brain barrier. However, an alternative approach
was to use L-dopa as dopamine’s immediate precursor,6,7
Movement Disorders, Vol. 00, No. 00, 2014 1
P E T E R A . L E W I T T
because it could transfer into the brain via a mechanism
of facilitated amino acid transport. Though only a small
fraction of a systemically-administered dose of L-dopa
enters the brain, this quantity proved to be sufficient for
restoring striatal dopaminergic neurotransmission.
L-dopa’s symptomatic control of parkinsonism was soon
joined by another pharmacological milestone, the devel-
opment of peripherally-acting decarboxylase inhibitors.
With these compounds (benserazide and carbidopa
[CD]), L-dopa’s systemic diversion to dopamine could be
blocked, thereby enhancing its CNS bioavailability, toler-
ability, and clinical effectiveness.8
The therapeutic concepts behind L-dopa treatment
might seem obvious, though managing PD with L-dopa
can be, at times, a frustrating exercise. Its pharm-
acology has been extensively investigated in over 5
decades of research, but much more remains to be
learned. In this article, some of the major accomplish-
ments and challenges still facing L-dopa therapeutics
are reviewed in the context of its pharmacodynamics
and pharmacokinetics.
L-dopa Therapy: More Than a
Dopamine Precursor
In 1970, at a time of great enthusiasm for the revo-
lutionary change in PD therapeutics, one of the pio-
neers of L-dopa therapy, Oleh Hornykiewicz, sounded
a note of concern about L-dopa that proved to be
extremely prescient:
. . .if L-dopa works in parkinsonism by replenishing
the missing dopamine in the striatum, then L-dopa is
quite obviously the most natural substance we can
have for treating what I should like to call “the stria-
tal dopamine deficiency syndrome.” However, it is
quite clear to me as a pharmacologist that, whatever
the mode and site of its action, L-dopa is far from
being perfect as a drug.”9
His early recognition of L-dopa’s limitations has been
borne out in everyday experiences by many PD patients
who, within a few years of starting treatment, experi-
ence inconsistencies in its benefits. A starting point for
understanding the problems associated with L-dopa ther-
apy is to shift the focus of inquiry beyond the actions of
dopamine created by L-dopa. The pathophysiology of
PD involves far more than a selective loss of striatal
dopaminergic signaling. Several neurotransmitter sys-
tems—among them, the other monoamine neurotrans-
mitters along with a number of compounds engaged in
neurotransmission and neuromodulation—also undergo
substantial depletion and altered functioning in the PD
brain. Combined interplay of these signaling compo-
nents results in the unique motor and behavioral features
of PD. For example, besides L-dopa, restoring motor
function in an experimental model of Parkinsonism (the
dopamine-depleted rat) requires the additional presence
2 Movement Disorders, Vol. 00, No. 00, 2014
of intact noradrenergic innervation.10 The implication
for PD therapeutics may be that effective L-dopa therapy
will need an additional restoration of norepinephrine
innervation for completely reversing motor and other
deficits.11
Another consideration for inquiry into the complex-
ity of PD treatments is that clinical responses to L-
dopa may be intermingled with ongoing compensatory
changes within the nigrostriatal pathway. At the ear-
liest stages of PD, for example, the remaining popula-
tion of dopaminergic neurons is thought to be
upregulated in synthesis, vesicular packaging, release,
and nerve terminal uptake of dopamine, as was
observed in experimental models of Parkinsonism.12
Hence, over time, a changing response to L-dopa
might be attributable to either a decline in the com-
pensatory responses or to further loss of nigrostriatal
projections (or both).
A half-century of investigating L-dopa neurochemis-
try has also expanded the identity of this molecule
beyond just a transient intermediate in the pathway of
catecholamine synthesis. Because L-dopa is not repre-
sented by a nucleic acid triplet codon, it lacks func-
tional roles related to incorporation into protein.
However, several unique physiologic actions have
been identified. One is that L-dopa serves directly as a
Ca11-dependent “classic” neurotransmitter. This
property has been observed in several brain regions
(including the CA1 hippocampus, the hypothalamic
supraoptic and paraventricular nuclei, and the tractus
solitarii).13 L-dopa also acts at other central nervous
system sites and with neuromodulatory properties dif-
fering from those of dopamine.14 Among these is
dose-related down-regulation of the enzyme that cata-
lyzes its conversion to dopamine, L-aromatic amino
acid decarboxylase (L-AAAD).15
Another important aspect of L-dopa pharmacology
has to do with its nonenzymatic conversion to several
biologically-active compounds. Among these are 2,4,5-
trihydroxyphenylalanine (TOPA) and TOPA-quinone,
each arising spontaneously from L-dopa in physiologi-
cal solutions.16 In addition to their excitotoxic proper-
ties (which can pose a threat to the survival of
dopaminergic neurons), these compounds may actually
function as an integral component of normal L-dopa
pharmacology. This possibility has been explored in
brain slice research demonstrating the production of
TOPA and TOPA-quinone immediately after L-dopa
administration.17 These compounds initiated various
neuronal responses in dopaminergic pathways (among
them increased neuronal firing, inward current flux,
and membrane depolarization) that were not attribut-
able to and preceded the other effects generated by
dopamine synthesis. As an indication of their excito-
toxic mechanism, the actions induced by TOPA and
 L E V O D O P A P H A R M A C O K I N E T I C S
TOPA-quinone could be blocked by administration of
a glutamate antagonist.17 L-dopa also can react non-
enzymatically to produce a conjugate with cysteine, 5-S-
cysteinyldopa. 5-Cysteinyldopa is a substrate for under-
going decarboxylation to form 5-S-cysteinyldopamine, a
pharmacologically-active compound that imparts oxida-
tive stress in dopaminergic neurons, where it also can
promote the aggregation of alpha-synuclein.18 These and
other studies highlighting the complexity of L-dopa’s
neuropharmacology indicate that we have a lot more to
learn about the actions of this drug in the PD brain.
Understanding clinical phenomena associated with
L-dopa such as dyskinesias and dose-by-dose fluctuations
also may benefit from recognition that this amino acid
behaves as more than just a dopamine precursor.
The Challenge for L-dopa Transport
to the Brain
L-dopa has a complicated path to travel in its gastro-
intestinal uptake and transfer to its site of action in
the brain. The facilitated absorption of L-neutral
amino acids such as L-dopa occurs in only a relatively
short territory of the duodenum and the proximal jeju-
num. L-dopa transportation uses sodium-dependent
L-neutral amino acid carrier system that is situated in
the gut wall and at the blood–brain barrier. At both
locations, L-dopa competes for uptake with other
L-neutral amino acids derived from the breakdown of
protein and other dietary sources of amino acids.19,20
Most of the load of orally-administered L-dopa is
cleared by first-pass hepatic metabolism or by distribu-
tion to skeletal muscle. Unless a catecholamine-O-
methyltransferase (COMT) inhibitor has been used, a
large fraction of an administered L-dopa dose under-
goes conversion to 3-O-methyldopa (as well as small
amounts of 4-O-methyldopa). These compounds,
which accumulate in the bloodstream to higher con-
centrations than those of typical L-dopa levels, also
can also compete with the uptake of L-dopa. Although
3-O-methyldopa has been generally regarded as meta-
bolically inert, some studies have shown it has
pharmacological activity at even neurotoxicity.21
Blocking the metabolism of L-dopa as it travels
from gut to brain has had practical applications for
improving clinical responses. Catecholamine-O-
methyltransferase inhibition with entacapone or tolca-
pone results in an extension of anti-Parkinsonian
effect by approximately 20 to 30 minutes for each
L-dopa dose. Each of these drugs at conventional dos-
age results in an approximately one-third increase of
L-dopa area-under the-time-plasma-concentration
curve (AUC).22 Although the COMT inhibitors offer
some useful extension of clinical effect against
wearing-off responses, these drugs at conventional
A N D P H A R M A C O D Y N A M I C S
dosage block less than half of systemic COMT activ-
ity. Drugs inhibiting systemic L-AAAD activity outside
of the CNS are also limited in the extent of their
actions. Although co-administration of CD or bensera-
zide can markedly decrease the systemic conversion of
23
L-dopa to dopamine, neither drug accomplishes full
inhibition when dosed at the conventional daily intake
of 75 to 100 mg.8 Supplemental CD can enhance or
accomplish further decarboxylase inhibition and, con-
sequently, increased L-dopa bioavailability.24 Like
COMT inhibition, this approach to diminishing the
first-pass metabolism of LD can provide some clinical
improvement, although generally not enough to abol-
ish motor fluctuations with immediate-release (IR)
L-dopa therapy. Human experiments testing an
increased dosage of supplemental CD or benserazide
have shown the inability of these drugs to achieve full
inhibition of L-AAAD activity.25,26
Enhancing Striatal Dopamine With
L-dopa
The unique role played by exogenously administered
L-dopa in generating dopamine arises from its entry
into the synthetic pathway past the physiological regu-
latory step for dopamine synthesis, tyrosine hydroxy-
lase. Even in advanced disease, when the PD brain has
lost most of its dopaminergic projections from sub-
stantia nigra to striatum, most investigations have
found sufficient L-AAAD activity remains for achiev-
ing rapid and thorough conversion of L-dopa to dopa-
mine. Where this enzymatic activity resides has been a
longstanding question. In the absence of dopaminergic
nerve terminals, the generation of striatal dopamine
from L-dopa might occur by means of L-AAAD
located in striatal serotonergic nerve terminals27; alter-
natively, enzymatic activity in various striatal inter-
neurons or even in glia might be responsible.28
The adequacy of remaining striatal L-AAAD activity
in advanced PD has been questioned as to a target for
improving L-dopa responsiveness when its clinical
effect seems to be on the decline. One line of investi-
gation has proposed improving the effectiveness of
L-dopa by augmenting the synthesis of L-AAAD in
striatum by means of a gene therapy intervention.
Application of this approach in a proof of concept
study in PD demonstrated the practicality of using
viral vector gene delivery to enhance L-AAAD activ-
ity.29 In these studies (which are in ongoing clinical
research), the initial findings showed improved consis-
tency of L-dopa clinical effect together with the dem-
onstration of increased enzymatic activity by PET scan
studies.30 Together with genes also for generating
tyrosine hydroxylase and its cofactor, introducing a
gene for augmenting L-AAAD synthesis into PD puta-
men has also been an intervention for a recent proof-
Movement Disorders, Vol. 00, No. 00, 2014 3
P E T E R A . L E W I T T
of-concept study, which showed that endogenous syn-
thesis of dopamine can be enhanced.31
The therapeutic concept underlying the use of mono-
amine oxidase type-B (MAO-B) inhibitors is for
extending the clinical actions from each dose of L-dopa
by retarding breakdown of the dopamine it produces.
This effect has been substantiated from extensive clini-
cal experience with MAO-B inhibitors that are mar-
keted or have been under clinical investigation.32
Besides MAO-B, other metabolic routes are involved in
the clearance of dopamine, however. The modest gains
that MAO-B inhibitors offer for the PD patient experi-
encing motor fluctuations have highlighted the need
for other strategies to achieve improved the constancy
of L-dopa effect.
L-dopa Pharmacokinetics and
Pharmacodynamics
One of the major pharmacodynamic challenges for
optimizing PD therapeutics is dealing with motor fluc-
tuations that commonly develop with orally-dosed
L-dopa. The repeated emergence of “off” states, which
for many patients with advanced PD can occupy up to
one-third or more of a typical waking day, is a prob-
lem of inadequate L-dopa delivery to the brain. Clini-
cal investigations have determined that providing
sufficient L-dopa to overcome Parkinsonism requires
exceeding a minimal threshold of circulating L-dopa
concentration to achieve reversal of signs and symp-
toms. Whereas “off” states can have other causes
besides insufficient L-dopa delivery (such as the phe-
nomenon of transient gait freezing), the most common
explanation for most motor fluctuations is nothing
more than inconsistency of L-dopa arriving at the
brain. In these circumstances, “off” episodes can be
eliminated during continuous intravenous or enteral
infusion of L-dopa.33 However, with current orally
administered L-dopa products, achieving regularity in
drug uptake to the brain is problematic. Even formula-
tions designed for achieving more sustained release of
L-dopa or concomitant inhibition of COMT have not
been particularly successful.34 The essence of the prob-
lem is that the human gastrointestinal tract is not well
suited for optimizing the uptake of orally administered
35
L-dopa. Episodic failure of L-dopa to provide benefit,
a common problem for many patients, has proved dif-
ficult to interpret amidst all the factors that influence
uptake and systemic handling of the drug.
To explore the systemic disposition of L-dopa and
the problems of consistent drug delivery, dozens of
L-dopa pharmacokinetic investigations have appeared
in the medical literature since the first clinical trials
with this drug. One of the most extensive investiga-
tions of L-dopa pharmacokinetics is a 1989 report com-
paring pharmacokinetic data from intravenous
4 Movement Disorders, Vol. 00, No. 00, 2014
administration of L-dopa and results from oral admin-
istration of both IR and sustained-release formula-
tions.36 In healthy volunteers, this study demonstrated
the rapid plasma clearance of L-dopa. Maximal con-
centration (Cmax) after two CD-L-dopa 25-100 IR tab-
lets was 1.39 6 0.34 mg/mL for L-dopa and 165 6 77
ng/mL for CD (which was absorbed more slowly than
L-dopa). For L-dopa, AUC was 3.69 6 0.74 mg h
21
21
mL . In the first hour after dosing, approximately
90% of orally administered L-dopa was taken up and
the process was near complete by 2 hours. Greater
delay in uptake was found with Sinemet CR, which
also had reduced bioavailability for both L-dopa and
CD. Other important observations were that CD
absorption was diminished in the presence of food and
that bioavailability of oral L-dopa in healthy young
controls (84% 6 13) was lower than in older PD sub-
jects (99% 6 21). Disposition kinetic parameters with
intravenous L-dopa showed an AUC (per mg L-dopa) of
21.7 ng hr21 mL21, an initial volume of distribution of
28.5 L, renal clearance of 72 mL/min, and plasma
clearance half-life of 1.8 hours (which was almost
doubled by the addition of CD). Renal excretion of L-
dopa accounted for approximately 10% of total clear-
ance. With oral administration of carbidopa-L-dopa
25/100 mg IR tablets, its time to maximal drug concen-
tration (Tmax) was 0.8 6 0.4 hours in this study
(Fig. 1).36 Co-administration of L-dopa with either ben-
serazide or CD results in extension of its Tmax by
approximately 30 minutes.37 Other investigations of
Tmax with oral dosing of IR CD-L-dopa have reported
this to be 1.1 6 0.7 hours38 and 1.0 6 0.1 hour.39 The
latter study found that the coefficient of variation for L-
dopa concentration over a dose cycle (standard devia-
tion/mean L-dopa concentration) was 68.8 6 3.7%.
A recent study of L-dopa population pharmacokinetics
compared findings using the CD/L-dopa 25/100 mg IR
formulation with those from administering an intesti-
nally-infused suspension of the drugs.40 Previously, both
one-compartment41,42 and two-compartment43 struc-
tural models have been used in carrying out L-dopa
pharmacokinetic analysis. In this population pharmaco-
kinetic study, a two-compartment structure provided
the best data fit for reporting on pharmacokinetic
parameter estimates and measures of their accuracy.40
The pharmacokinetics of L-dopa do not change sys-
tematically during up to 4 years of chronic treat-
ment,44 nor are there alterations of L-dopa disposition
in PD patients who experience motor fluctuations as
compared with those with consistent L-dopa effects.45
Several studies have confirmed that the pharmacoki-
netics of L-dopa exhibit considerable inter-subject vari-
ability. Postmenopausal women show much greater
L-dopa bioavailability (AUC from a single dose of IR
CD-L-dopa, 25-100 mg) than men of similar age. This
finding was evident even after adjustment for
 L E V O D O P A
FIG. 1. Pharmacokinetics of L-dopa (left panel) and carbidopa (right panel) in 16 fasted healthy young volunteers. Data are mean plasma concentra-
tions (61 standard deviation) after oral administration of immediate-release CD-L-dopa 25-100 mg (2 tablets). Data taken from Yeh and colleagues
(Fig. 1).36
sex-related differences attributable to body weight.
The mean L-dopa Tmax did not differ between men
and women, however.46 Some of the major influences
on pharmacokinetic parameters are likely related to
the stomach’s ability for efficient transfer of the drug
to the absorptive surfaces of the duodenum and proxi-
mal jejunum. In general, this function is delayed in PD
patients as compared with healthy controls.47,48 Gas-
tric emptying is further slowed by an effect conferred
by L-dopa itself.49
Some investigations have reported that gastric Heli-
cobacter pylori infection is a factor contributing to
motor fluctuations, and that improvement in consis-
tency of L-dopa effect occurs once the infection is
eradicated.50,51 However, a recent study of L-dopa
pharmacokinetics in PD patients both with and with-
out Helicobacter pylori infection does not confirm
that disposition of L-dopa is necessarily changed by
presence of the infection.52 Another factor interfering
with L-dopa uptake and associated with motor fluctua-
tions is bacterial overgrowth occurring in the small
intestine. After antibiotic treatment to restrict bacterial
growth in the small intestine, motor fluctuations can
improve.53
Gastric “housekeeping” function can be influenced
by everyday experiences that can alter stomach empty-
ing, such as pH change by administration of antacids
or proton pump inhibitors. Intake of iron or other
divalent metals (which chelate L-dopa) also can inter-
fere with L-dopa uptake. Dietary factors such as fat
and L-neutral amino acid content contribute to
decreased L-dopa bioavailability and lower Cmax while
increasing Tmax.54,55 Other influences on orally-dosed
P H A R M A C O K I N E T I C S A N D P H A R M A C O D Y N A M I C S
L-dopa pharmacokinetics include increased values of
Cmax and AUC as correlates of both low body mass
and increased age.56,57
For most patients experiencing dose-by-dose fluctua-
tions, monitoring of their plasma L-dopa concentration
provides a close correlate of the observed anti-
parkinsonian effect. Several studies have used timed
motor tasks as surrogates of parkinsonism (such as
timed walking and finger tapping) to demonstrate
pharmacokinetic–pharmacodynamic relation-
ships.38,44,45 In these circumstances, a typical L-dopa
plasma concentration for initiating reversal of parkin-
sonism effect is in the range of 0.8 to 1.1 mg/mL (4.1-
5.6 mM). With administration of IR L-dopa (together
with adequate dosage of decarboxylase inhibitor), the
duration over which the drug’s plasma concentration
exceeds the “on” threshold is close to that of the
clearance half-life of IR CD-L-dopa— typically,
approximately 3 hours. The onset of clinical effect is
not exactly coincident with the timing of changes in
plasma L-dopa concentration; a hysteresis function has
been demonstrated in which anti-parkinsonian actions
lag by approximately 15 minutes.38 The prediction of
clinical effects from measurements of plasma L-dopa
concentration (such as timed hand tapping or walking)
fit best to nonlinear modeling of the pharmacokinetic
data.58,59 Correlations between Tmax and motor
responses can vary greatly, as can the timing of onset
of observed beneficial effects. For example, in one
study of IR CD-L-dopa (Fig. 2),60 the Tmax for maxi-
mal improvement in timed hand tapping was 2.3 6 0.9
hours, whereas the Tmax for global motor improve-
ment was 1.1 6 0.6 hours.60
Movement Disorders, Vol. 00, No. 00, 2014 5
P E T E R A . L E W I T T
FIG. 2. Pharmacodynamic modeling of actual and modeled mean
effect measurements versus mean plasma L-dopa concentration for
eight PD subjects receiving two doses (at 4-hour intervals) of
controlled-release CD-L-dopa 50-200 mg (Sinemet CR 50-200).60
Immediately after blood sampling, tapping rate (the number of times in
60 seconds subjects alternately tapped levers placed 25 cm apart),
walking rate (time required to arise from a seat, walk 6 m, turn, and
return to a sitting position), and global parkinsonism rating (using a 25
to 0 scale of parkinsonian features [0 denoting normal movement
capability and 25 signifying severe parkinsonism] and a 11 to 15 rat-
ing for dyskinesia [with 11 denoting minimal involuntary movements
and 15 indicating severe dyskinesia]). Global scores were treated as
continuous variables. Walking and global rating scores were fitted
best to a sigmoid Emax pharmacodynamic model, whereas tapping
scores were fitted best to an Emax model. Plasma L-dopa concentra-
tions were modeled with effect measures using extended least-
squares regression analysis. The EC50 (half-maximal effective concen-
tration) values for walking and global scores were identical, whereas
the EC50 for tapping score was substantially greater. Reproduced
from Nelson and colleagues (Fig. 1).60
For some PD patients (especially in the first years
after start of L-dopa therapy), relief of parkinsonian
signs and symptoms persists without fluctuation and
irrespective of the rise and fall in circulating drug con-
centration. Symptomatic control of parkinsonism in
these circumstances—sometimes referred to as the
“honeymoon” period—makes optimization of therapy
easy to accomplish. However, by 2 or more years after
the start of L-dopa therapy, this pattern of response
6 Movement Disorders, Vol. 00, No. 00, 2014
commonly is replaced by motor fluctuations that occur
regularly over a cycle corresponding to the half-life of
L-dopa plasma clearance (3 hours). Like L-dopa
plasma concentrations, the clinical effects also can be
capricious from dose to dose. The reason for the tran-
sition of L-dopa’s clinical effects is not well under-
stood. Observations of L-dopa treatment outcomes
have discerned two pharmacodynamic patterns after
L-dopa dosing: the “short-duration” response (SDR)
and the “long-duration” response (LDR). Along with
dyskinesias, these response patterns came to be recog-
nized shortly after the introduction of L-dopa.61 They
can be manifested by the same patient. The SDR,
which is characterized by a cycle of improvement of
parkinsonian control over a period of 3 to 5 hours
during dosing with IR CD/L-dopa, can be shown to
parallel the timing of rise and fall in circulating drug
concentration. This pattern appears to be the direct
translation into clinical effect of L-dopa delivered to
the striatum. In contrast, the LDR does not seem to
follow the plasma concentration of L-dopa and persists
for hours to days after the drug has been stopped.62
Evidence for the LDR also can be discerned during
therapy with dopaminergic agonists, indicating that a
mechanism specific to dopamine synthesis, vesicular
packaging, release, or re-uptake mechanisms is
unlikely to be involved.63 The time-course of LDR
undergoes a much slower evolution than the SDR,
sometimes requiring up to several weeks for its full
expression. Other phenomena can distinguish the two
patterns of L-dopa response: in patients experiencing
dyskinesias, for example, these emerge during the
cycle of a SDR but not as a feature of the LDR.64
Close investigation of L-dopa–treated patients has esti-
mated that, of the drug’s total anti-parkinsonian
effect, the SDR constitutes between one third and one
half, whereas the rest originates from the LDR.63
The mechanism by which the SDR is enacted seems
easier to conceptualize than the enigmatic LDR. To
those searching for an explanation of the LDR, the
sustained improvement of parkinsonian features as a
feature of LDR stands in contrast to the known phar-
macology of dopaminergic neurotransmission. The
LDR cannot arise from a retained CNS depot of
dopamine or its precursor, because L-dopa undergoes
rapid turnover in the mammalian brain.65 Nor is
there evidence for upregulation of dopamine receptor
sensitivity as a possible explanation. Another possibil-
ity is that of a downstream effect mediated initially
by dopaminergic stimulation and resulting in activa-
tion of transcription factors and cascades of
immediate-early gene proteins (such as FosB, Jun-B,
c-Fos, and Zif268).66,67 Possibly LDR might originate
from remodeling of striatal outflow pathways as a
consequence of nonphysiological dopaminergic
 L E V O D O P A P H A R M A C O K I N E T I C S
replacement therapy, as has been hypothesized for the
development of L-dopa–induced dyskinesias.68
Another explanation for what might constitute the
LDR arises from the realm of learning theory, with
demonstration that L-dopa therapy leads to enhanced
capability for integrating “chunks” of information
into more sustained sequences.69
Among the highlights of L-dopa pharmacokinetic-
pharmacodynamic research is a detailed analysis of
extensive pharmacokinetic data from standardized
2-hour intravenous L-dopa infusions (at 1 mg/kg body
weight per hour).43 The goal of this datamining was
to understand within-subject variability in L-dopa
plasma concentrations. From analysis of data from
multiple L-dopa infusions, conducted repeatedly during
intervals of 4 years,44 the authors found that two-
compartment rather than one-compartment models
tended to fit the pharmacokinetic data better. They
concluded that a large fraction of between-subject var-
iability in plasma L-dopa concentration could be
explained by body weight. Also, the variability in pre-
dicted peak plasma L-dopa concentrations could be
largely explained by variation in L-dopa’s central com-
partment volume in the two-compartment model. The
authors summarized their analysis of L-dopa pharma-
cokinetic parameters and within-subject variability
(using data from as many as 10 pharmacokinetic stud-
ies conducted in the same individuals) with the conclu-
sion that these results could not be explained by either
a systematic (predictable) change in association with
the increasing years or parkinsonism, or else random
occurrence. A prior study of these pharmacokinetic
findings showed no change over the first 4 years of
L-dopa treatment as an explanation for the evolution
of motor fluctuations.44
Conclusions
For all its imperfections as a pharmaceutical, orally
administered L-dopa continues to be the major treat-
ment option for managing PD.70 With conventional
formulations of L-dopa, irregular absorption and
rapid catabolism are the basis for many of the prob-
lems associated with its chronic use. Extensive study
of L-dopa pharmacology has provided evidence that
this drug behaves as more than just a transient meta-
bolic intermediate in the pathway of catecholamine
synthesis. Optimal dosing regimens can vary greatly
among PD patients, as can the interplay of SDR and
LDR. Several marketed L-dopa products purport to
offer more continuous dopaminergic stimulation than
the IR formulation. However, pharmacokinetic analy-
sis of Sinemet CR (Merck and Co., Inc., Whitehouse
Station, NJ, USA), Madopar HBS (F. Hoffmann-La
Roche AG, Basel, Switzerland), and Stalevo (Novartis
AG, Basel, Switzerland) has shown that none of them
A N D P H A R M A C O D Y N A M I C S
provides reliable consistency of therapeutic concen-
trations of L-dopa.33,34 There is a promising future
for improving L-dopa therapy with products currently
under development. These options include a new
sustained-release oral CD–L-dopa formulation,71 two
72,73
L-dopa pro-drugs, two gastric-retentive slow-
release L-dopa formulations,74,75 an inhaled L-dopa
delivery system,76 and a subcutaneous infusion system
using solubilized CD and L-dopa.77 These products
will join intestinally infused CD–L-dopa gel, a formu-
lation currently marketed in Europe and elsewhere,
and currently awaiting US regulatory approval.
Although this L-dopa formulation offers fine control
of plasma L-dopa concentration,33 drug administra-
tion by means of a tube through the stomach wall is
not a practical treatment option for most patients
experiencing motor fluctuations.
The unmet needs of L-dopa therapeutics call for a
more detailed understanding of how this drug works.
The relative contributions of daily L-dopa intake, dura-
tion of drug exposure, and severity of parkinsonian
features has been difficult to tease out in explaining
the development of dose-by-dose fluctuations (i.e., loss
of the LDR) and dyskinesias. A recent study that com-
pared outcomes from starting L-dopa in Ghanaian and
Italian PD patients observed that motor fluctuations
and dyskinesias did not develop as correlates of L-dopa
use duration but, rather, in association with the extent
of disease progression.78 The message from this study
(as from several other investigations3) is that, in mild
PD, delaying the start of L-dopa is unwarranted as a
means for better long-term benefits from this drug.
Some of the most pressing questions for improving PD
outcomes include how the initial “honeymoon period”
of L-dopa therapy can be sustained, and how to avoid
the development of dyskinesias. Fortunately, there is
no shortage of curiosity among researchers for advanc-
ing today’s knowledge about L-dopa’s pharmacology
into future treatment for PD.
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