Pharmacokinetic-pharmacodynamic relationship of levodopa with and without tolcapone in patients with Parkinson's disease.

OBJECTIVE: To investigate the effect of administration of the catechol-Omethyltransferase (COMT) inhibitor tolcapone on the concentration-effect relationship of levodopa in patients with advanced Parkinson's disease and on-off fluctuations. DESIGN: Nonblind single-group 2-period pharmacokinetic-pharmacodynamic study. PATIENTS AND PARTICIPANTS: 12 patients, mean age 59 years, with idiopathic Parkinson's disease and response fluctuations. METHODS: The pharmacokinetics [plasma concentrations of levodopa and 3-O-methyldopa (3-OMD)] and motor effects [global score of the Columbia University Rating Scale (CURSsigma)] of levodopa (plus the peripheral decarboxylase inhibitor benserazide 1:4) were determined for 4 consecutive dosage intervals (4 hours each, starting at 8.00am) in 12 patients before (day 1) and during (day 8) coadministration of tolcapone 100 mg 3 times daily for 7 days. RESULTS: Under tolcapone, exposure to levodopa [area under the plasma concentration-time for the dosage interval (AUCt)] observed for the separate doses increased by 1.6- to 2.2-fold, and peak plasma drug concentrations (Cmax) increased by 1.1 - to 2.1 -fold. 3-OMD concentrations at day 8 were reduced to about 20% of the values at day 1. At baseline (day 1, before the first levodopa dose), CURSsigma averaged 40 +/- 10 points. After the first levodopa dose. CURSsigma declined to 20 +/- 9 points. At day 8. the predose CURSsigma decreased to a final score of 31 +/-13 points, and the maximal decline after the first levodopa dose was to a final score of 16 +/- 8 points. Population analysis (NONMEM) of the concentration-effect relationship of levodopa according to a sigmoidal Emax model and over all dosage intervals did not show differences in levodopa responsiveness with or without tolcapone. The population mean of the 50% effective concentration (EC50) of levodopa was 1350 microg/L with an standard error of the population parameter estimate of 18%: adding tolcapone treatment as a covariate did not significantly change the population fit. Circadian influences on levodopa respon- siveness were not evaluable by the NONMEM model due to overparametrisation, but visual inspection of plotted data did not suggest differences in the concentration-effect relationship between the 4 consecutive dosage intervals on days 1 and 8. CONCLUSIONS: The gain in clinical improvement with levodopa under tolcapone can be fully explained by tolcapone-induced changes of peripheral levodopa pharmacokinetics. We suggest that this interaction study, performed in patients and using clinical data, excludes any central effects of tolcapone or any inhibiting effect of 3-OMD on levodopa permeation through the blood-brain barrier, which otherwise would have led to a decrease in the EC50 of levodopa.     

Effect of age on the pharmacokinetics of oral levodopa in patients with Parkinson's disease

Summary The influence of age on the kinetics of a standard oral dose of levodopa administered with an inhibitor of peripheral dopa decarboxylase enzymes (benserazide) has been evaluated in 40 patients with Parkinson's disease (age 34–78 y) on chronic therapy. They were divided into 2 groups, on the basis of age below (21 patients, Group A) or above (19 patients, Group B) 65 y.The area under the plasma concentration-time curve (AUC) of levodopa was significantly greater in the older group (547 versus 428 mol·1^–1·min in Group B), coupled with a reduced apparent oral clearance (8.1 versus 10.7 ml·min^–1 ·kg^–1) and a longer plasma elimination half-life (67.6 versus 54.6 min). The age of the patients was positively correlated with the AUC of levodopa (r=0.474) and its plasma elimination half-life (r=0.391), and was negatively correlated with clearance (r=–0.489).The findings confirm previous data on volunteers that showed a reduction in the systemic clearance of levodopa due to age, which would probably account for the finding of a greater AUC of levodopa in older patients. The observed, age-mediated differences in levodopa pharmacokinetics, albeit statistically significant, were moderate and were likely to be of only minor importance for the dosing schedule.This work was part of the Progetto finalizzato Invecchiamento of the National Research Council of Italy, Grant No. 912012     

卡比多巴-左旋多巴控释片对帕金森患者睡眠障碍的改善作用

目的 探讨卡比多巴-左旋多巴控释片对帕金森病(PD)患者睡眠障碍的改善作用.方法 选取2013年6月至2015年6月本院神经科收治的伴有睡眠障碍的PD患者69例,随机分为观察组39例和对照组30例.观察组卡比多巴-左旋多巴控释片治疗,对照组艾司唑仑治疗.比较两组治疗前后病情Hoehn-Yahr分期评估差异,对两组进行多导睡眠监测,比较两组睡眠情况,并采用睡眠评价量表(ESS)及匹茨堡睡眠质量指数量表(PSQI)评分评估患者睡眠障碍的改善效果.结果 治疗前,观察组、对照组Hoehn-Yahr分期评估、多导睡眠监测睡眠潜伏期、觉醒次数、觉醒时间、ESS、PSQI评分比较,差异均无统计学意义(P＞0.05);治疗后,观察组Hoehn-Yahr分期评估为(1.49±0.72)级,显著低于对照组(P＜0.05),睡眠潜伏期[(25.40±12.12) min]、觉醒次数[(3.21±2.11)次]、觉醒时间[(30.02±10.05)min]均比对照组显著减少(P＜0.05),ESS、PSQI评分均显著低于对照组(P＜0.05);治疗期间,两组均未出现明显的不良反应.结论 与艾司唑仑卡相比,卡比多巴-左旋多巴控释片治疗PD伴睡眠障碍患者效果更显著,可显著改善患者睡眠障碍,进而提高患者生活质量.     

帕金森病患者外周血肿瘤坏死因子水平变化

目的通过检测帕金森病（PD）患者外周血中肿瘤坏死因子-α（tumor necrosis factor-alpha,TNF-α）,探讨TNF-α在PD患者外周血中的变化。方法采用放射免疫分析方法,对84例（PD组）患者和87例（对照组）健康对照的血TNF-α进行检测;同时对PD患者的年龄、性别、疾病分期和病程进行组内比较。结果PD患者与健康对照者TNF-α含量分别为（14.7±2.3）pmol/L、（16.9±4.4）pmol/L,差异有统计学意义（P〈0.01）;按患者年龄、性别、疾病分期和病程进行组内比较差异无统计学意义（P〉0.05）。结论PD发病过程中存在着免疫系统失调,PD患者外周血TNF-α减少,而且与年龄、性别、疾病分期和病程无关。     

普拉克索与多巴丝肼治疗帕金森病的成本效果分析

目的 比较单用多巴丝肼与合用普拉克索治疗帕金森病两种方法效果.方法 采用对照研究方法,比较多巴丝肼治疗组(A组)及合用普拉克索治疗组(B组)的治疗效果及治疗成本.结果 B组虽然在药物费用及治疗费用方面较A组明显增加(P＜0.01),但其帕金森病综合量表评分显著下降(P＜0.05),而且在帕金森病各期均可应用.结论 联合应用普拉克索虽会加重药物成本及治疗成本,但在改善帕金森病各期临床症状方面效果更好,且可应用于不同分期的帕金森病患者,应个体化推荐.     

Pharmacokinetics of levodopa/carbidopa delivered from gastric-retentive extended-release formulations in patients with Parkinson's disease

The investigators conducted a single-dose pharmacokinetic (PK) study of levodopa/carbidopa delivered from novel gastric-retentive extended-release (ER) tablets versus a comparator ER tablet (M-ER) in patients with Parkinson's disease. Two levodopa/carbidopa (200 mg/50 mg) gastric-retentive ER formulations (4 hours and 6 hours) and M-ER were administered orally with food. Blood samples were collected for up to 24 hours post dose to determine levodopa and carbidopa concentrations. Tolerability was assessed by monitoring adverse events and measuring vital signs. PK modeling was conducted to estimate the release characteristics for future gastric-retentive ER formulations to achieve a less fluctuating plasma concentration profiles. Compared with M-ER, both gastric-retentive ER formulations exhibited a longer time to reach a lower maximal plasma concentration for levodopa and carbidopa. The 4-hour formulation demonstrated a similar area under the concentration-time curve compared with M-ER, whereas the 6-hour formulation demonstrated a lower area under the concentration-time curve. All formulations were well tolerated. Modeling suggests that a gastric-retentive ER formulation with a longer release duration administered twice daily may achieve a less fluctuating levodopa concentration profile than M-ER administered 3 times daily. This study demonstrates that gastric-retentive ER dosage forms may reduce dose frequency while minimizing the plasma peak-to-trough fluctuation and consequently reduce motor fluctuation in patients with Parkinson's disease.     

Pharmacokinetics and effects of levodopa in advanced Parkinson's disease

Summary Five patients with severe Parkinson's disease were characterized with respect to their pharmacokinetic and pharmacodynamic responses to levodopa given: orally, intravenously (three different infusion rates) and intraduodenally. The best therapeutic infusion rate in the intravenous study was used for the intraduodenal infusion of levodopa. A lag time between plasma concentration and effect following oral administration was seen in three of the five patients and this disequilibrium was estimated as the rate constant k_e0 using model-independent analysis.The plasma concentration-effect relationship was similar for the three modes of administration and in all patients the therapeutic plasma concentration for full mobility was >4–5 g·ml^–1. The disequilibrium half-life for development of effect after oral administration was calculated to be about 30 min.The patients remained clinically stable during the period of the intraduodenal infusion.     

Effect of duration of levodopa/decarboxylase inhibitor therapy on the pharmacokinetic handling of levodopa in elderly patients with idiopathic Parkinson's disease

Summary We address, from a pharmacokinetic viewpoint, the important question of why some patients with clinical idiopathic Parkinson's disease experience a fall off in benefit from levodopa maintenance therapy.Thirteen such patients, of mean age 78 y, without overt fluctuations in motor control in temporal relation to dosing with a levodopa/decarboxylase inhibitor combination, were studied. Levodopa (currently 400 to 800 mg daily) had been started at between 61 and 81 y of age, the mean duration of therapy being 54 months. Plasma concentrations of levodopa and its peripheral metabolite, 3-0-methyldopa, were measured before a morning dose of levodopa (100 mg)/carbidopa (25 mg) and at hourly intervals for 6 h after.There was a significant negative regression between duration of levodopa therapy (but not age or severity of disease) and the area under the plasma concentration/time curve (AUC) for levodopa attributed to the test dose. A significant negative regression was also seen of duration of therapy on the dose absorbed per unit distribution volume, but not on the elimination rate constant, indicating a decrease in bioavailability and/or an increase in distribution volume with duration. There was a tendency for the plasma 3-0-methyldopa concentration, standardised for daily dose, [30MD], to increase with duration of therapy. Although, the regression of duration on [30MD] did not reach statistical significance, that on the ratio, [30MD]/AUC, did so at the 0.01 level.The amount by, and time for which, the plasma levodopa concentration exceeds any critical threshold for the competitive active uptake process into the brain may thus decrease with duration of therapy. This may explain in part the limited reversal of the neurological deficit, which is more typical of later onset Parkinsonism, and, possibly, the decrement in biological half time with duration of therapy, typical of early onset disease. 3-0-Methyldopa is known to compete for active uptake with levodopa; the ratio, [30MD]/AUC, may be a measure of this competition. Intrinsic activity of neuronal uptake mechanisms, capacity of the basal ganglia for storage of dopamine, and post synaptic neuronal activity may, of course, also be determinants of clinical outcome.     

Clinical and pharmacokinetic comparison of oral and duodenal delivery of levodopa/carbidopa in patients with Parkinson's disease with a fluctuating response to levodopa

Summary The clinical effects and pharmacokinetics of orally and intraduodenally administered levodopa, in four patients with Parkinson's disease have been compared. The patients had unpredictable fluctuations in motor function and episodic unresponsiveness to single doses of levodopa. The pharmacokinetic and clinical data of these patients were compared retrospectively with those of Parkinsonian patients with fluctuations in motor performance but with preserved clinical responses to single oral doses of levodopa.There was a threshold plasma concentration of levodopa associated with the switch on or off effect. In addition, rapid attainment of this critical plasma concentration was associated with a quicker onset of action and a more prolonged clinical response.All the patients had delayed absorption of levodopa related to delayed and erratic gastric emptying, which contributed to the fluctuation in motor response. In contrast, the patients with fluctuating motor effects but a preserved clinical response after levodopa showed an absorption pattern comparable to that of four patients studied after duodenal delivery of levodopa.It is suggested that there is a subgroup of patients with fluctuating responses due mainly to altered peripheral pharmacokinetics of levodopa. The findings demonstrate the relevance of routine measurements of plasma levodopa in patients with Parkinson's disease in whom there are fluctuations in motor performance.     

Plantago ovata Mucilage in the Design of Fast Disintegrating Tablets

In the present work, fast disintegrating tablets of prochlorperazine maleate were designed with a view to enhance patient compliance by direct compression method. In this method mucilage of Plantago ovata and crospovidone were used as superdisintegrants (2-8% w/w) along with microcrystalline cellulose (20-60% w/w) and directly compressible mannitol (Pearlitol SD 200) to enhance mouth feel. The prepared batches of tablets were evaluated for hardness, friability, drug content uniformity, wetting time, water absorption ratio and in vitro dispersion time. Based on in vitro dispersion time (approximately 8 s), the two formulations were tested for the in vitro drug release pattern (in pH 6.8 phosphate buffer), short-term stability (at 40°/75% relative humidity for 3 mo) and drug-excipient interaction (IR spectroscopy). Among the two promising formulations, the formulation prepared by using 8% w/w of Plantago ovata mucilage and 60% w/w of microcrystalline cellulose emerged as the overall best formulation (t_50% 3.3 min) based on the in vitro drug release characteristics compared to conventional commercial tablets formulation (t_50% 17.4 min). Short-term stability studies on the formulations indicated that there are no significant changes in drug content and in vitro dispersion time (p<0.05).     

The pharmacokinetics of intravenous and oral levodopa in patients with Parkinson's disease who exhibit on-off fluctuations.

We have studied the clinical effects and pharmacokinetics of levodopa infusions and oral therapy in seven patients with Parkinson's disease. They all showed on-off fluctuations whilst receiving long-term treatment with levodopa in combination with a peripheral decarboxylase inhibitor. Intravenous infusion at a constant rate for up to 16 h resulted in a smoother clinical response, and maintained plasma levodopa concentrations within narrower limits compared with conventional oral therapy. Following infusion rates of 32-80 mg h-1 (0.5-1.3 mg kg-1 h-1) the plasma concentration associated with optimum therapeutic response lay between 0.3 and 1.6 mg l-1. There was considerable variation in the oral absorption and elimination of levodopa, both within and between subjects. The concentration of 3-OMe dopa in plasma hardly increased during each day's levodopa therapy. In all cases levels were greater than the maximum concentrations of levodopa, sometimes by as much as a factor of 10. In contrast to most previous reports on the pharmacokinetics of levodopa, the data presented here are consistent with a two-compartment kinetic model. It is not known whether the difference in pharmacokinetics is due to chronic therapy or whether it is specific to those patients who show on-off phenomena, but such changes might be related in some way to the development of fluctuations in clinical response.     

司来吉兰联合左旋多巴治疗帕金森病 51例

目的 观察司来吉兰联合左旋多巴治疗帕金森病(PD)的临床疗效及其对PD病人帕金森病评分量表(UPDRS)评分、血清β淀粉样蛋白1-42(Aβ1-42)水平及平衡能力的影响.方法 选取2018年6月至2019年8月在重庆医科大学附属遂宁市中心医院就诊的PD病人102例,采用随机数字表法分为观察组和对照组各51例,对照组予以左旋多巴治疗,观察组予以司来吉兰联合左旋多巴治疗,治疗2个月后进行疗效评价,并比较两组病人治疗前后血清Aβ1-42水平、UPDRS评分、Berg平衡量表(BBS)评分、跌倒效能量表(MFES)评分、害怕跌倒(FOF)例数及生活质量综合评价量表(SF-36)评分变化情况.结果 治疗后,观察组总有效率显著高于对照组(94.12％比76.47％,P<0.05);治疗后观察组血清Aβ1-42水平[(1.32±0.42)μg/L比(1.27±0.45)μg/L]、BBS评分[(47.05±4.16)分比(45.31±4.01)分]、MFES评分[(97.22±10.46)分比(89.52±10.75)分]及SF-36评分[(68.54±7.22)分比(61.37±7.46)分]均高于对照组,UPDRS评分[(25.36±1.54)分比(31.33±1.62)分]及FOF例数[8例比18例]均低于对照组(P<0.05).结论 司来吉兰联合左旋多巴治疗PD效果显著,可有效缓解病人病情,改善临床症状.     

The levodopa wearing-off phenomenon in Parkinson's disease: pharmacokinetic considerations

Levodopa is the most efficacious treatment in the management of Parkinson's disease. Unfortunately, chronic use of traditional levodopa/dopa decarboxylase inhibitor formulations is associated with the development of complications, such as wearing-off and dyskinesia. In an attempt to avoid these complications, some physicians delay the introduction of levodopa or employ levodopa-sparing strategies; however, these strategies are frequently suboptimal for patients. As most patients require the superior efficacy of levodopa during the course of their disease, an appreciation of the changing response to levodopa over time and an understanding of the pharmacokinetic principles underlying the development of complications such as wearing-off is essential in the long-term management of the patient.     

Hydrosoluble fiber (Plantago ovata husk) and levodopa II: experimental study of the pharmacokinetic interaction in the presence of carbidopa.

Levodopa combined with carbidopa constitutes one of the most frequent medication in the treatment of Parkinson's disease. Plantago ovata husk (water-soluble fiber) improves levodopa absorption conditions, but when this drug is administered with carbidopa, fiber could reduce its effectiveness. The purpose of this study is to investigate whether the presence of P. ovata husk modifies in rabbits the bioavailability and other pharmacokinetic parameters of levodopa (20 mg/kg) when administered by the oral route with carbidopa (5 mg/kg). We have also studied whether pharmacokinetic modifications are fiber-dose dependent (100 and 400 mg/kg). When levodopa and carbidopa were administered with 100 mg/kg P. ovata husk, the value of AUC for levodopa diminishes 29.7% (sign, n=6, P<0.05) and Cmax 28.1% (sign, n=6, P<0.05) in relation to the values obtained when these drugs were administered without fiber. If the dose of fiber was 400 mg/kg, the decrease was smaller: 20.4% for AUC (no significant difference) and 24.6% for Cmax (sign, n=6, P<0.05), that may indicate an inhibitory action of AADC by the fiber or any of its partial hydrolysis products. On the other hand, since certain time on, levodopa concentrations are always higher in the groups that receive fiber: 210 min with 100 mg/kg and 150 min with 400 mg/kg. The administration of P. ovata husk with levodopa/carbidopa to patients with Parkinson disease could be beneficial and in particular in those patients who also suffer constipation due to an improvement of levodopa kinetic profile with higher final concentrations, a longer plasma half-life and lower Cmax.     

天麻钩藤颗粒联合左旋多巴治疗帕金森病的疗效观察

目的观察天麻钩藤颗粒联合左旋多巴治疗帕金森病的临床疗效。方法选取2015年7月—2016年6月监利县人民医院收治的帕金森患者88例,随机分为对照组和治疗组,每组各44例。对照组口服左旋多巴片,125 mg/次,2次/d,每周调整药物用量,逐渐增量至250 mg/次,3次/d,每日总剂量不超过6 g;治疗组在对照组的基础上口服天麻钩藤颗粒,5 g/次,3次/d。两组均治疗3个月。治疗后,观察两组的临床疗效,比较两组日常生活能力和运动能力评分和不良反应情况。结果治疗后,对照组和治疗组的总有效率分别为61.36%、72.27%,两组比较差异有统计学意义(P0.05)。治疗后,两组日常生活能力和运动能力评分均显著下降,同组治疗前后比较差异有统计学意义(P0.05);且治疗组这些评分明显低于对照组,两组比较差异具有统计学意义(P0.05)。两组不良反应发生率比较差异无统计学意义。结论天麻钩藤颗粒联合左旋多巴治疗帕金森病,临床疗效确切,症状改善明显,值得临床推广。     

Alternatives to levodopa in the initial treatment of early Parkinson's disease

Parkinson's disease (PD) is primarily a disease of elderly patients. This article reviews current knowledge and recent developments relating to drugs that can be used as alternatives to levodopa as initial treatment of PD. Synthetic orally acting dopamine agonists have found increasing favour as an option for early PD in relatively young patients. This strategy is based on evidence that this approach may delay the onset of motor fluctuations, at least during the first 5 years of treatment. Subcutaneous apomorphine infusions may attenuate motor fluctuations in late-stage disease, and transdermal rotigotine, a dopamine agonist in development, has also been shown to be efficacious. The greater proclivity for dopamine agonists to cause psychotoxicity has, however, limited their routine use in the elderly. Selective monoamine oxidase type B (MAO-B) inhibitors, used as monotherapy, delay the need for the introduction of levodopa by about 9 months. These agents appear to be less efficacious than dopamine agonists but are better tolerated. Concern has been expressed about the potential of the MAO-B inhibitor selegiline (deprenyl) to induce cardiovascular adverse effects (orthostatic hypotension), either directly or through its amphetamine catabolites. Rasagiline is a new MAO-B inhibitor that is not broken down to amphetamine derivatives and is indicated as both monotherapy in early PD and as adjunctive therapy in PD patients with motor fluctuations. Two older classes of agents have undergone a resurgence of interest in recent years. Amantadine, which enhances dopaminergic transmission and has antiglutamate activity, is occasionally used as monotherapy but has recently been widely used as an antidyskinetic agent in late-stage PD. Anticholinergic drugs, such as benztropine (benzatropine) and orphenadrine also provide control of symptoms when used as monotherapy, but their psychotoxic, cognitive and autonomic adverse events make them inappropriate for the treatment of the elderly.Effective therapy in PD should prevent disease progression and abolish motor and cognitive handicap. Currently, none of the existing drugs meets all these needs.     

Motor complications, levodopa metabolism and progression of Parkinson's disease

INTRODUCTION: Oxidative stress is an essential component of neuronal death in Parkinson's disease (PD). Clinically, progression of PD is also characterised by onset of motor complications (MC). MC results from the peripheral and central degree of fluctuations of levodopa (LD) and of dopamine. AREAS COVERED: This review highlights aspects of LD and dopamine metabolism in chronic neurodegeneration in PD. A Medline search (terms: homocysteine, LD, PD, progression [from 2000 onwards]) was performed and considered preclinical and clinical investigations. The author discusses pharmacokinetic and metabolic aspects of chronic LD administration in PD patients and provides a therapeutic concept to reduce probable PD accelerating consequences of chronic LD application. EXPERT OPINION: The author suggests that the future 'ideal' oral LD therapy should be homocysteine-reducing, methyl-group-donating, oxidative-stress-decreasing and antiglutamatergic while also allowing continuous delivery to the brain. This may slow the progression of PD and delay the onset of MC, both of which represent unmet needs in the treatment of PD patients.     

Cost analysis of ropinirole versus levodopa in the treatment of Parkinson's disease

BACKGROUND: Not all patients with Parkinson's disease (PD) respond to levodopa and others develop dyskinesias. Ropinirole, a dopamine agonist, is associated with fewer dyskinesias than levodopa. OBJECTIVE: To examine the economic impact of reducing dyskinesias using ropinirole instead of levodopa plus benserazide in PD was examined. The research question addressed was: is the added cost of ropinirole offset by savings due to avoided cases of dyskinesia? METHODS: A cost-minimisation analysis was performed from both the societal and Ministry of Health (MoH) of Ontario, Canada perspectives, using 5-year data from a study of dyskinesia outcomes comparing ropinirole with levodopa plus benserazide. A predictive model was developed to capture resource utilisation over 5 years, such as medication costs, medical consultations, hospital admissions, nursing home admissions, caregiver time and productivity loss. The model was based on a previously reported clinical trial which determined dyskinesia rates to be 20% for ropinirole and 45% for levodopa. Standard costing lists were used, and costs were discounted at various rates. Constant 1999 Canadian dollars ($Can) were applied, and no increases were assumed over the time horizon of the analysis. A multivariate sensitivity analysis with changes in key parameters was also performed. RESULTS: From a societal perspective, ropinirole was cost saving. From the MoH perspective, the analysis yielded an incremental expected daily cost/patient of $Can4.41 for substituting levodopa plus benserazide with ropinirole. Ropinirole resulted in daily savings/patient of $Can0.17 in non-drug healthcare costs. In the sensitivity analysis, the direction of results did not change despite changes of 15 to 20% in key parameters, suggesting robustness of the model. CONCLUSIONS: From the societal perspective, in comparison with levodopa plus benserazide, the added cost of ropinirole is offset by savings due to avoided cases of dyskinesia.     

The pharmacokinetics and pharmacodynamics of levodopa in the treatment of Parkinson's 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.