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The pathophysiology underlying the fluctuations in response following oral levodopa therapy is complex and includes peripheral and central factors. The short half-life of levodopa, erratic gastrointestinal absorption, and competitive transport across the blood–brain barrier have been regarded as factors responsible for the fluctuating plasma and striatal concentrations of levodopa. Indeed, failure of an oral dose to produce an effect or delay in the onset of action have been associated with problems in absorption.1,2
We studied the pharmacokinetics of levodopa in 19 patients with advanced Parkinson’s disease (12 men, seven women; period of evolution of illness more than 10 years) with and without a delayed response to the first drug dose in the morning (delayed early morning turn “ON”). The patients were selected according to the UK Brain Bank criteria; those who could not tolerate an assessment after 12 hours without taking their antiparkinsonian medication were excluded. All patients signed an informed consent form before being included in the study.
Medication and food were withheld after midnight the night before the study day. All patients’ regular therapeutic first (morning) levodopa/carbidopa dose was between 125 mg and 250 mg. Therefore all patients received a single oral dose of levodopa/carbidopa (250/25 mg) at 9:00 am, to ensure that all had a response. A low protein breakfast was served three hours after drug administration.
Blood samples were collected every 20–30 minutes for six hours following drug administration. Plasma levodopa concentration was determined using high performance liquid chromatography (HPLC) with electrochemical detection as previously described.3 Peak plasma concentration (Cmax), the time elapsed to reach the Cmax, area under the curve, half-life, clearance, and slope in the absorption phase (Kabs) were determined using PK Solutions version 2 software (Summit, USA http://www.summitpk.com/). Motor performance was evaluated using a tapping test on the more affected side. In this test, patients are requested to alternately tap two points separated by a distance of 30 cm with the fingers of the hand (of the most affected side) for one minute. In the present study, total tapping—that is, the number of times the patient is able to carry out the task, was recorded every 20 minutes during the first two hours and then every 30 minutes until the completion of the test. The Unified Parkinson’s Disease Rating Scale for motor examination (UPDRS-III) was applied prior to (baseline) and at the time of the “best on” after levodopa administration. Delayed early morning turn “ON” was defined as the condition in which the effect of levodopa in the tapping test (a 50% basal score improvement; maximal levodopa effect = 100%) appeared more than 40 minutes after the administration of the drug.
For all patients, the results are given as mean (SD) and Student’s t test (p<0.05) was used to determine the significance between the differences.
The UPDRS-III and tapping tests were used to verify the occurrence of the drug effect, thus allowing patients with and without delayed early morning turn “ON” to be distinguished. In clinical practice, a standard dose of levodopa becomes effective within the first 20 minutes after drug administration. For separating the patients without and with delayed early morning turn “ON”, the latter were considered as those in whom a standard levodopa dose took more than 40 minutes to become effective. These patients showed a tendency to have worse baseline and best ON scores than the patients without delayed early morning turn “ON”, although this trend was not statistically significant.
As shown in fig 1, a significant difference was found between the Cmax values of patients without delayed early morning turn “ON” (mean 3552 (SD 1208) ng/ml) and those of patients with delayed response (1146 (289) ng/ml). None of the other pharmacokinetic parameters showed statistically significant differences.
To obtain an adequate response in Parkinson’s disease the appropriate oral dose of levodopa is usually determined bearing in mind that worse symptoms may be treated with higher drug dosages or more frequent doses as long as side effects do not appear. This simplistic approach does not take into account the evolution of the disease, in which not only do the symptoms become more evident but also the treatment progressively loses its effectiveness. Indeed, patients with Parkinson’s disease, whose illness has evolved over several years and evidence motor fluctuations tend to show a delayed response to the first oral levodopa dose compared with patients with non-fluctuating motor symptoms. The mechanism of this phenomenon is still poorly understood.4 In the present study, patients with delayed early morning turn “ON” had significantly lowered Cmax values. Even though we are unable to give a direct explanation for the molecular events underlying this finding, it is clear from our data that the pharmacokinetics of levodopa play an important role in the occurrence of delayed early morning turn “ON”.
Since all other pharmacokinetic parameters (including Kabs) of the patients with and without delayed response showed no differences, one might consider that the rate of absorption is basically the same in both groups. In addition, it has been found that both subcutaneous administration of apomorphine5 and pyloric bypass with duodenal infusion of levodopa6 are useful because they reduce plasmatic variability and improving clinical response in patients with delayed early morning turn “ON” by increasing functional “ON” time with less dyskinesia and fluctuation. Therefore, we propose that altered gastric emptying but not the intestinal absorption rate might be linked to the delay in the clinical response observed. However, further studies are necessary to address this issue.
Slower progression of the neurodegenerative process and the loss of levodopa effect are usually associated with the degeneration of dopaminergic nerve terminals in the central nervous system (pharmacodynamic factor).7 The data presented here highlight the need to also consider pharmacokinetic factors when analysing the delayed early morning turn “ON” condition and considering the best doses and regimen of drug administration in patients with advanced Parkinson’s disease.
The authors greatly appreciate the excellent technical assistance provided by Angélica Fierro.
This study was financially supported by an educational grant from Laboratorio Chile to the Universidad de Santiago de Chile.
Competing interests: none declared