Levodopa Concentrations Research Articles

Amperometric Detection of 3-(3,4-Dihydroxyphenyl)-l-alanine (l-Dopa) in Raw and Cooked Mucuna Bean Seeds Employing Micro-HPLC

Amperometric detection of 3-(3,4-dihydroxyphenyl)-l-alanine (l-dopa) on a glassy carbon electrode at oxidation potential of +0.70 V in Mucuna pruriens after micro-high performance liquid chromatography separation is reported. Optimised eluent consisted of 0.87 mM 1-octane sulphonic acid sodium salt, 18.2 mM citric acid, and 82.8 mM sodium acetate with pH adjusted to 2.18 using 85% orthophosphoric acid. Detection of low concentrations of l-dopa up to 5.12 ng mL−1 was achieved. The method was employed to determine l-dopa in raw and cooked beans after water extraction through a 0.45 μm membrane with no further sample treatment.

The Pharmacokinetics and Pharmacodynamics of Levodopa in the Treatment of Parkinsons Disease

Levodopa, a prodrug of dopamine, remains to be one of the main drugs in the treatment of Parkinson's disease. All current levodopa products are formulated with aromatic amino acid decarboxylase inhibitors such as carbidopa or benserazide to prevent the metabolism of levodopa in the gastrointestinal tract and systemic circulation. Levodopa pharmacokinetic profiles remain unchanged after multiple doses, and are similar between healthy volunteers and patients and among patients at different stages of disease. Entacapone inhibits the metabolism of levodopa therefore increases the area under the plasma concentration-time profile of levodopa; however, it may decrease the initial absorption rate of levodopa in some patients probably due to competitive absorption. Food appears to affect the absorption of levodopa, but its effects vary with formulations. The results of positron emission tomography study suggest that a high protein diet may compete with the uptake of levodopa into the brain, therefore, may result in reduced levodopa effects. Since infusion studies demonstrated that it is beneficial to maintain stable plasma concentrations of levodopa, controlled-release formulations have been designed to provide prolonged absorption of levodopa. However, subsequent pharmacokinetic and pharmacodynamic studies demonstrated that a threshold concentration of levodopa appears to be necessary to switch patients "on". Once patients are turned "on", the duration of levodopa effects may be correlated with plasma concentration of levodopa. As such, more recent studies have demonstrated significant clinical benefits such as shorter time to "on" and longer duration of "on" when combining the immediate- and controlled-release levodopa products as compared to controlled-release levodopa products. Given these findings, it is important for physicians to understand the relationship between the pharmacokinetics and pharmacodynamics of levodopa in order to provide dosage regimens that meet patient needs. The pharmacokinetics and pharmacodynamics data of levodopa reported in the literature are reviewed here.

Motor fluctuations in Parkinson's disease

Almost all patients with Parkinson's disease will eventually require levodopa during the course of their disease. The effectiveness of levodopa is evident, but earlier use and higher doses are causative of the emergence of motor fluctuations. About one half of patients develop motor fluctuations 4–6 years after starting levodopa therapy for parkinsonian symptoms. Peripheral and central pharmacokinetic mechanisms are related to motor fluctuations. It was reported that time to peak concentration (Tmax) and elimination half-life (T1/2) of levodopa decreased especially in patients with wearing-off (peripheral pharmacokinetics). On the other hand, there are several reports demonstrating no change in peripheral pharmacokinetics in patients on long-term levodopa therapy. The reduced capacity for presynaptic storage of dopamine by nigral neurons is believed to be another important factor responsible for motor fluctuations (central pharmacokinetics). In addition, a mathematical model that was recently established based on the hypothesis that dopamine release is subject to probabilistic variations in the quantity of dopamine has indicated that motor fluctuations might be explained by presynaptic mechanisms. On the other hand, several studies demonstrated that changes in postsynaptic mechanisms (pharmacodynamics) play an important role in shortening the duration of levodopa action in advanced stages. In clinical practice therapeutic strategies for motor fluctuations are focused on continuous dopaminergic stimulation at postsynaptic dopamine receptors. Once motor fluctuations appear, therapeutic regimens should be individualized to retain optimal control of the symptoms based on accurate assessment of each patient's levodopa cycle and responses to drugs. Symptom diaries kept by patients or caregivers are useful for this purpose.

Determination of l-dopa using electropolymerized 3,3′,3″,3‴-tetraaminophthalocyanatonickel(II) film on glassy carbon electrode

Electropolymerized film of 3,3′,3″,3‴-tetraaminophthalocyanatonickel(II) (p-Ni IITAPc) on glassy carbon (GC) electrode was used for the selective and stable determination of 3,4-dihydroxy- l-phenylalanine ( l-dopa) in acetate buffer (pH 4.0) solution. Bare GC electrode fails to determine the concentration of l-dopa accurately in acetate buffer solution due to the cyclization reaction of dopaquinone to cyclodopa in solution. On the other hand, p-Ni IITAPc electrode successfully determines the concentration of l-dopa accurately because the cyclization reaction was prevented at this electrode. It was found that the electrochemical reaction of l-dopa at the modified electrode is faster than that at the bare GC electrode. This was confirmed from the higher heterogeneous electron transfer rate constant ( k 0) of l-dopa at p-Ni IITAPc electrode (3.35 × 10 −2 cm s −1) when compared to that at the bare GC electrode (5.18 × 10 −3 cm s −1). Further, it was found that p-Ni IITAPc electrode separates the signals of ascorbic acid (AA) and l-dopa in a mixture with a peak separation of 220 mV. Lowest detection limit of 100 nM was achieved at the modified electrode using amperometric method. Common physiological interferents like uric acid, glucose and urea does not show any interference within the potential window of l-dopa oxidation. The present electrode system was also successfully applied to estimate the concentration of l-dopa in the commercially available tablets.

Possible role for chlorpheniramine in the treatment of l-DOPA induced dyskinesia in Parkinson’s disease

Dopamine (DA) replacement therapy with L-3,4-dihydroxyphenylalanine (L-DOPA) remains the most effective medication for the symptomatic relief of Parkinson’s disease (PD). However, chronic L-DOPA treatment is often complicated by a variety of involuntary movements, termed L-DOPA-induced dyskinesia (LID), which represents one of the major limitations in the treatment for PD. Depending on clinical presentation and chronology after a dose of L-DOPA, LID can be classified in peak-dose, diphasic, and off period dyskinesias. Peak-dose dyskinesia occurs at the time of the highest brain concentration of LDOPA and represents the most common type of LID. The current pharmacological treatment of this form of dyskinesia involves, as a first measure, the reduction of individual L-DOPA doses, which indeed can lead to improvement of dyskinesia, exacerbating however the symptoms of the disease. Slow-release L-DOPA preparations or spreading of the daily dose of L-DOPA into smaller but more frequent doses has been also used; however, only limited improvements have been reported so far. On the other hand, the only currently available drug with an evidence-based recommendation for dyskinesia is the glutamate antagonist amantadine, even though no large scale study of this drug has been conducted. Moreover, only a number of patients can tolerate effective doses of amantadine, and its effects decline over time. Finally, dyskinesias that become disabling must often be managed surgically, despite the high cost and risk for serious adverse events of such intervention. Thus, it is a common belief that the development of new safe and effective therapies that treat dyskinesias without aggravating parkinsonism are urgently needed. A rapid and excessive increase in extracellular DA, after L-DOPA administration, is considered one of the major causes for peak-dose LID. This is due to the fact that oral formulations of L-DOPA have short plasma half-lives, so each dose causes a rapid increase followed by a rapid decrease in striatal dopamine levels, leading to intermittent stimulation of striatal dopamine receptors. Interestingly, in experiments with rats, administration of 8-hydroxy-2-(d-npropylamino) tetralin (8-OH-DPAT), a selective 5-HT1A receptor agonist, attenuated the increase in L-DOPA-induced extracellular DA [1] while alleviated L-DOPA induced motor complications, including LID [2]. In support of a role in receptor specificity, it was shown that these effects of 8-OH-DPAT were mediated mainly via stimulation of 5-HT1A receptors, since co-administration of a 5HT1A receptor antagonist (WAY100635) abolished the above mentioned effects of 8-OH-DPAT [1]. Moreover, in compliance with these animal studies, the use of the clinically available 5-HT1A agonist sarizotan, in the context of a multicenter trial, was proved to be effective in the treatment of LID in PD patients [3]. Taken together, all these data suggest that pharmaceutical agents capable of stimulating 5-HT1A receptors could avert the induction of L-DOPA induced motor complications in patients with PD. P. N. Karamanakos P. Pappas M. Marselos Department of Pharmacology, Medical School, University of Ioannina, Ioannina 451 10, Greece

Synthesis and Study ofl-Dopa−Glutathione Codrugs as New Anti-Parkinson Agents with Free Radical Scavenging Properties

A series of novel molecular combinations (1-4), in which L-dopa (LD) is linked covalently via an amide bond with glutathione (GSH), were synthesized and evaluated as potential anti-Parkinson agents with antioxidant properties. These conjugates were characterized by evaluating solubility, chemical and enzymatic stabilities, and apparent partition coefficient (log P). Derivatives 2 and 4 were tested for their radical scavenging activities, by use of a test involving the Fe(II)/H2O2-induced degradation of deoxyribose. In this study, the antioxidant efficacy of codrugs 1 and 3 was also assessed through the evaluation of plasmatic activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx). Furthermore, the central nervous effects and rat striatal concentration of LD and dopamine (DA) have been evaluated after oral administration of codrugs 1 and 3. Tested compounds prolonged the plasma LD levels and were able to induce sustained delivery of DA in rat striatum with respect to an equimolar dose of LD. The results suggest that compounds 1 and 3 could represent useful new anti-Parkinson agents devoid of the pro-oxidant effects associated with LD therapy and potentially able to restore the GSH depletion evidenced in the substantia nigra pars compacta (SNpc) of PD patients.

Duodenal levodopa infusion for the treatment of Parkinson’s disease

Motor fluctuations are a common problem in the long-term management of Parkinson’s disease (PD), resulting in disability and impaired quality of life. The relatively short serum half-life (∼ 90 min) of oral levodopa/carbidopa and its erratic absorption due to delayed and inconsistent gastric emptying (a non-motor feature of PD) are thought to be important factors in the development of motor fluctuations. Continuous infusion of levodopa/carbidopa directly into the small intestine of PD patients results in marked reduction of motor fluctuations by reducing plasma levodopa variability by an order of magnitude over oral therapy. Previously, the use of long-term intraduodenal infusion of levodopa/carbidopa was limited by the relatively large volumes of infusate necessitated by the low solvency of levodopa. The development of a micronized levodopa (20 mg/ml) and carbidopa (5 mg/ml) suspension utilizing a methylcellulose gel provides the high levodopa concentration and physical and chemical stability necessary for long-term enteral therapy. Clinical evidence indicates that a marked reduction of motor fluctuations and dyskinesias can be achieved and maintained by intraduodenal administration of this suspension. This article reviews the published data describing the efficacy and safety of duodenal levodopa, and discusses its current and potential role in meeting the needs of PD patients.

Role of catechol structure in the adsorption and transformation reactions of L-DOPA in soils.

3-(3',4'-Dihydroxyphenyl)-L-alanine (L-DOPA), which is synthesized in velvet bean (Mucuna pruriens), inhibits plant growth. The concentration of L-DOPA in soil is reduced by adsorption and transformation reactions, which can result in the reduction of its plant-growth-inhibitory activity. To determine which part of the L-DOPA structure is involved in the adsorption and soil transformation reactions, we compared the kinetics of L-DOPA disappearance in a volcanic ash soil with that of L-phenylalanine (3-phenyl-L-alanine) and L-tyrosine (3-(4'-hydroxyphenyl)-L-alanine), compounds that are similar in structure to L-DOPA but do not have a catechol (o-dihydroxybenzene) moiety. L-Phenylalanine and L-tyrosine were not adsorbed and transformed in the soil at equilibrium pH values between 4 and 7. These results suggest that the adsorption and transformation reactions of L-DOPA in the soil involve the catechol moiety and not the amino and carboxylic acid groups, which are common to all three compounds. Like L-DOPA, (+)-catechin, another allelochemical that contains a catechol moiety, underwent adsorption and soil transformation reactions. Thus, we concluded that the concentrations of allelochemicals bearing a catechol moiety in soils will decrease rapidly owing to adsorption and transformation reactions, and this decrease will be faster in soils with a high pH value or high adsorption ability. Owing to this decrease in concentration, allelopathic phenomena may not occur.

L-DOPA (l-3,4-dihydroxyphenylalanine) affects rooting potential and associated biochemical changes in hypocotyl of mung bean, and inhibits mitotic activity in onion root tips

A study was undertaken to explore the effect of l-DOPA (l-3,4-dihydroxyphenylalanine) on the rooting potential of hypocotyl cuttings of mung bean (Phaseolus aureus Roxb. var. SML-32) and related biochemical changes at the post-expression phase. At lower concentrations of (0.0001–0.1 mM) l-DOPA, there was no change in rooting potential, though the average number of roots per cutting and root length were significantly decreased (except at 0.0001 mM). However, at 1.0 mM concentration, a 50% inhibition in rooting potential was noticed and the root number and length were severely reduced. In contrast, at 2.5 mM l-DOPA, none of the hypocotyl cutting rooted. The decrease in rooting potential was associated with a significant effect on the biochemical changes measured in terms of protein and carbohydrate metabolism and activity of peroxidases. In the l-DOPA treated hypocotyl cuttings, there was a significant reduction in the protein and carbohydrate content, whereas activities of associated enzymes proteases and amylases decreased, particularly at higher treatment concentration (>1.0 mM). It indicated negative effect of l-DOPA on these two important metabolic processes. Likewise, activity of peroxidases also decreased in the l-DOPA treated hypocotyl mung bean cuttings thereby indicating its role in suppressing rhizogenesis as the enzyme is involved in lignification process during cell division. l-DOPA suppressed mitotic activity in the root tip cells of onion indicating thereby its interference with the cell division, which is required for the formation of new meristematic tissue during rhizogenesis. Based on the obtained results, it is concluded that l-DOPA interferes with the various biochemical processes in the mung bean hypocotyl cuttings thereby affecting their rooting potential.

Effect of ionizing radiation on antinutritional features of velvet bean seeds ( Mucuna pruriens)

Impact of gamma irradiation on the antinutritional constituents of seeds of Mucuna pruriens was assessed on exposing to doses of 2.5, 5.0, 7.5, 10, 15 and 30 kGy. Except for 2.5 kGy, the rest showed significant dose-dependent increase in phenolics. Tannin concentration did not differ significantly up to 7.5 kGy, while it significantly increased at higher doses. Excluding 2.5 kGy, the rest of the treatments showed significant decreases in the phytic acid and complete degradation was attained at 15 and 30 kGy. The l-DOPA concentration showed a dose-dependent decline. A trace amount of hemagglutination activity was seen on human erythrocytes in raw seeds, which was completely absent on irradiation (>5 kGy). Concentration of Polonium-210, a natural radionuclide falls within the admissible limits for consumption. As Mucuna seeds serve as food, feed or as pharmaceuticals, it may be necessary to set the ionizing radiation to a specific dose to retain optimum levels or to eliminate phenolics, tannins, phytic acid and L-DOPA. As irradiation is a physical and cold process, it may be ideal and emerge as an important technique to improve the nutritional or pharmaceutical quality of Mucuna seeds and its products.

Simultaneous determination of benserazide and levodopa by capillary electrophoresis–chemiluminescence using an improved interface

A capillary electrophoresis coupling with indirect chemiluminescence detection method for the simultaneous determination of benserazide and levodopa has been developed. The detection interface was improved to simplify the capillary electrophoresis–chemiluminescence (CE–CL) system and the features of this improved interface were illustrated in this paper. The CE–CL conditions for the simultaneous determination of benserazide and levodopa were optimized. Under the optimal conditions, the CL intensity was linear with concentrations of levodopa in the range of 1.0 to 100.0 μg ml −1, and benserazide in the range of 10.0 to 1000 μg ml −1, respectively. The detection limits (S/N = 3) in turn were 1.85 μg ml −1 for BS and 0.12 μg ml −1 for L-dopa with relative standard deviations of less than 3%. The proposed method has been successfully applied to the determination of benserazide and levodopa in medopar tablets and spiked urine samples, demonstrating the feasibility and reliability of the proposed method.

Effects of caffeine on levodopa pharmacokinetics and pharmacodynamics in Parkinson disease

The authors studied the acute effect of caffeine on the levodopa pharmacokinetics and pharmacodynamics in 12 patients with idiopathic Parkinson disease. This double-blind, randomized, crossover study revealed that caffeine shortened the maximal plasma concentration of levodopa, decreased the latency to levodopa walking and tapping motor response, and increased the magnitude of walking response. Caffeine administered before levodopa may improve its pharmacokinetics in some parkinsonian patients.

Intravenous levodopa administration in humans based on a two-compartment kinetic model

Levodopa, when combined with a decarboxylase inhibitor, essentially delivers dopamine directly to the brain, with no net effect on brain blood vessels. For future neuroimaging studies of Parkinson disease and Tourette syndrome, we sought to rapidly produce a biologically relevant levodopa concentration in plasma and then maintain that concentration long enough to assess motor, cognitive, emotional, and neuroimaging responses, while minimizing side effects in levodopa-naive individuals. Based on available pharmacokinetic data and a two-compartment model, we designed a decreasing-exponential-rate infusion to meet these goals. This report gives results of double-blind levodopa and placebo infusions in six healthy subjects. Mean plasma levodopa concentrations were within 3% of their 1200 ng/mL target at 20 and 40 min into the infusion, and within 20% between ∼12 and 90 min. Levodopa significantly reduced serum prolactin and raised serum growth hormone concentrations. Volunteers had no significant side effects.

An electrochemical sensor for l-dopa based on oxovanadium-salen thin film electrode applied flow injection system

An oxovanadium-salen complex ( N,N′-ethylene-bis(salicylideneiminato) oxovanadium) thin film deposited on a graphite–polyurethane electrode was investigated with regard to its potential use for detection of l-dopa in flow injection system. The oxovanadium(IV)/oxovanadium(V) redox couple of the modified electrode was found to mediate the l-dopa oxidation before its use in the FIA system. Experimental parameters, such as pH of the carrier solution, flow rate, sample volume injection and probable interferents were investigated. Under the optimized FIA conditions, the amperometric signal was linearly dependent on the l-dopa concentration over the range 1.0 × 10 −6 to 1.0 × 10 −4 mol L −1 ( I anodic μA) = 0.01 + 0.25 [ l-dopa μmol L −1]) with a detection limit (S/N = 3) of 8.0 × 10 −7 mol L −1 and a sampling frequency of 90 h −1 was achieved. For a concentration of 1.0 × 10 −5 mol L −1 l-dopa, the R.S.D. of nine consecutive measurements was 3.7%.

Pharmacokinetics of L-dopa

According to our data in rats, peripheral 3.4-dihydroxyphenylalanine (DOPA) kinetics are similar to striatal DOPA and dopamine kinetics. The measurement of plasma l-3.4-dihydroxyphenylalanine (L-dopa) concentration is thus useful to predict dopamine kinetics in the striatum and to treat the motor fluctuations of parkinsonian patients. In patients with Parkinson’s disease (PD), long-term L-dopa therapy accelerated DOPA absorption and steepened features of L-dopa pharmacokinetics. In the senile-onset group, the pharmacokinetic pattern did not change even after long-term L-dopa therapy. The frequency of motor fluctuations is much lower in senile-onset patients with PD than in middle-onset patients. Differences in the pattern of L-dopa pharmacokinetics in the two groups may explain why the senile-onset group rarely develops ‘wearing-off’, even after long-term L-dopa therapy. L-dopa is transported by a saturable active transporter system, called the LNAA (large neutral amino acid) system, in the gut and blood brain barrier. L-dopa absorption is thus affected by food intake, especially a proteinrich diet. The slope of the time-concentration curve for L-dopa administered before a meal is steeper than if it is administered after a meal. Considering that pulsative stimulation of L-dopa may cause motor fluctuations, L-dopa should be given after meals whenever possible, even if it necessitates a higher L-dopa dose.

Production of l-DOPA using Cu-alginate gel immobilized tyrosinase in a batch and packed bed reactor

In this study, production of l-DOPA ( l-3, 4-dihydroxy phenylalanine) was investigated by using tyrosinase enzyme in batch and packed bed reactors. Tyrosinase has been immobilized with method of entrapment in copper-alginate gels. l-DOPA concentration obtained from batch reactor for free and immobilized enzyme was 9.5 and 4.5 mg/L, respectively. l-DOPA concentration was obtained as 1.2 mg/L in the packed bed reactor. When air was introduced l-DOPA production increased 6.4 times in packed bed reactor and the productivity was calculated as 110 mg/L h.

Modified high-performance liquid chromatography with electrochemical detection method for plasma measurement of levodopa, 3-O-methyldopa, dopamine, carbidopa and 3,4-dihydroxyphenyl acetic acid

Plasma measurements of levodopa and its major metabolites including dopamine and 3-O-methyldopa have been limited by cumbersome methods and poor sensitivity within relatively narrow ranges of plasma levels. We now report a modification of an HPLC method that permits concomitant measurements of a wide range of concentrations of levodopa, dopamine (DA), carbidopa, 3-O-methyldopa (3-OMD) and 3,4-dihydroxyphenyl acetic acid (DOPAC) from one HPLC injection. The recoveries ranged from 77 to 107% with an intra-day precision around 5% (CV) and inter-day CV's about 10-20%. This validated method will simplify pharmacokinetic studies of levodopa and its metabolites for mechanistic studies or therapeutic clinical monitoring which play a crucial role in development of strategies to prolong motor benefits from individual doses and reduce involuntary movements called dykinesias.

Role of striatal l‐DOPA in the production of dyskinesia in 6‐hydroxydopamine lesioned rats

We explored possible differences in the peripheral and central pharmacokinetics of L-DOPA as a basis for individual variation in the liability to dyskinesia. Unilaterally, 6-hydroxydopamine (6-OHDA) lesioned rats were treated chronically with L-DOPA for an induction and monitoring of abnormal involuntary movements (AIMs). Comparisons between dyskinetic and non-dyskinetic cases were then carried out with regard to plasma and striatal L-DOPA concentrations, tissue levels of dopamine (DA), DA metabolites, and serotonin. After a single intraperitoneal injection of L-DOPA, plasma L-DOPA concentrations did not differ between dyskinetic and non-dyskinetic animals, whereas peak levels of L-DOPA in the striatal extracellular fluid were about fivefold larger in the former compared with the latter group. Interestingly, the time course of the AIMs paralleled the surge in striatal L-DOPA levels. Intrastriatal infusion of L-DOPA by reverse dialysis concentration dependently induced AIMs in all 6-OHDA lesioned rats, regardless of a previous priming for dyskinesia. Steady-state levels of DA and its metabolites in striatal and cortical tissue did not differ between dyskinetic and non-dyskinetic animals, indicating that the observed difference in motor response to L-DOPA did not depend on the extent of lesion-induced DA depletion. These results show that an elevation of L-DOPA levels in the striatal extracellular fluid is necessary and sufficient for the occurrence of dyskinesia. Individual differences in the central bioavailability of L-DOPA may provide a clue to the varying susceptibility to dyskinesia in Parkinson's disease.

Polysomnographic and pharmacokinetic findings in levodopa‐induced augmentation of restless legs syndrome

Augmentation, defined as a loss of circadian recurrence with progressively earlier daily onset and increase in the duration, intensity, and anatomy of symptoms, not compatible with the half-life of the drug, is associated with dopaminergic treatment in restless legs syndrome (RLS) patients. The pathogenesis of augmentation is unclear. We describe a patient with idiopathic RLS who developed augmentation after 8 months of levodopa treatment. Videopolysomnographic and pharmacokinetic studies with monitoring of plasma levodopa levels demonstrated marked motor hyperactivity during augmentation, with anarchic discharges of motor unit potentials, tonic grouped discharges and flexor spasms, associated with painful dysesthesia. Symptoms and signs of augmentation were related to low plasma levodopa levels, abating 75 minutes after oral levodopa administration and reappearing after 3 hours, closely mirroring the rapid rise and fall of plasma levodopa concentration. This case is the first report in which RLS augmentation is shown to be characterized by motor hyperkinesias paralleling levodopa plasma pharmacokinetic profile.

Pharmacokinetic Optimisation in the Treatment of Parkinson???s Disease

Pharmacotherapy for Parkinson's disease is focused on dopaminergic drugs, mainly the dopamine precursor levodopa and dopamine receptor agonists. The elimination half-life (t(1/2)) of levodopa from plasma (in combination with a decarboxylase inhibitor) of about 1.5 hours becomes more influential as the disease progresses. The long-duration of response to levodopa, which is evident in early Parkinson's disease, diminishes and after a few years of treatment motor performance is closely correlated to the fluctuating plasma concentrations of levodopa. Absorption of levodopa in the proximal small intestine depends on gastric emptying, which is erratic and may be slowed in Parkinson's disease. The effects of levodopa on motor function are dependent on gastric emptying in patients in the advanced stages of disease. The current treatment concept is continuous dopaminergic stimulation (CDS). Sustained-release formulations of levodopa may provide more stable plasma concentrations. Oral liquid formulations shorten the time to reach peak concentration and onset of effect but do not affect plasma levodopa variability. The t(1/2) of levodopa can be prolonged by adding a catechol-O-methyltransferase inhibitor (entacapone or tolcapone), which may reduce fluctuations in plasma concentrations, although both peak and trough concentrations are increased with frequent administration. Intravenous and enteral (duodenal/jejunal) infusions of levodopa yield stable plasma levodopa concentrations and motor performance. Enteral infusion is feasible on a long-term basis in patients with severe fluctuations. Among the dopamine receptor agonists the ergot derivatives bromocriptine, cabergoline, dihydroergocryptine and pergolide, and the non-ergot derivatives piribedil, pramipexole and ropinirole, have longer t(1/2) compared with levodopa. Thus, they stimulate dopamine receptors in a less pulsatile manner, yet pharmacokinetic studies of repeated doses of dopamine receptor agonists are few. Optimisation of these drugs is often performed with standardised titration schedules. Apomorphine and lisuride have short t(1/2) and are suitable for subcutaneous infusion, with results similar to those of levodopa infusion. Transdermal administration of dopamine receptor agonists such as rotigotine might be an alternative in the future. In general, initial dopamine receptor agonist monotherapy is associated with poorer motor performance and lower incidence of motor complications compared with levodopa. Buccal administration of the monoamine oxidase-B inhibitor selegiline (deprenyl) provides better absorption and less formation of metabolites compared with standard tablets. To conclude, several new drugs, formulations and routes of administration have been introduced in the treatment of Parkinson's disease during the last decade, mainly with CDS as the aim. CDS can be approached by optimising the use of dopaminergic drugs based on pharmacokinetic data.