Gender and pramipexole effects on levodopa pharmacokinetics and pharmacodynamics

The authors studied the pharmacokinetics of levodopa (LD) with and without pramipexole (PPX) in men and postmenopausal women with PD. Patients on stable dose of carbidopa/LD were randomized to receive escalating doses of placebo or PPX over 7 weeks. LD and PPX pharmacokinetics were performed after a single test dose 25/100 of carbidopa/LD, before initiation of PPX or placebo, at 1.5 mg/d and 4.5 mg/d of PPX or placebo. Compared to men, women had greater LD bioavailability. PPX did not alter LD bioavailability, and PPX pharmacokinetics were equivalent in men and women.     

The effect of exercise on levodopa absorption.

We studied the effect of exercise using cycle ergometry on levodopa absorption in ten patients with Parkinson's disease. Oral levodopa was administered during exercise and at rest on separate days. Exercise delayed levodopa absorption in five patients, increased it in three, and did not influence it in two. We conclude that exercise can either increase or decrease levodopa absorption.     

On-off phenomenon: relation to levodopa pharmacokinetics and pharmacodynamics

Motor function in the moderately to severely affected parkinsonian patient is critically dependent upon delivery of levodopa to the striatum. This, in turn, is influenced by the fluctuating plasma concentrations of levodopa produced by the drug's short half-life and erratic absorption, and by modifiable transport at the blood-brain barrier. Duration of response to a single dose of levodopa is proportional to peak plasma drug levels, and paradoxical responses may occur when plasma concentrations are in the vicinity of minimum effective concentrations. Thus the strategy of administering frequent, small doses of levodopa may contribute additional unpredictability to a fluctuating clinical response imposed by pharmacokinetic factors.     

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.     

The effect of tolcapone on levodopa pharmacokinetics is independent of levodopa/carbidopa formulation

Clinical pharmacology studies have shown that the catechol-O-methyltransferase inhibitor tolcapone increases the bioavailability area under the plasma concentration-time curve (AUC) and the plasma elimination half-life (t _1/2) of levodopa. The objective of the study was to evaluate the pharmacokinetics of levodopa and 3-O-methyldopa (3-OMD) after coadministration of tolcapone 200 mg with levodopa/carbidopa in the following doses: 100/10 mg, 100/25 mg, 200/20 mg, 200/50 mg, 250/25 mg (all immediate-release) and 200/50 mg (controlled-release). Thirty healthy male volunteers were divided into four groups: three groups of 8 and one group of 6. Participants in the first three groups received two formulations of levodopa/carbidopa. Each dose was administered on two occasions, once with tolcapone 200 mg andonce with placebo (four-way crossover). In the fourth group, one formulation was given on two occasions, once with tolcapone 200 mg and oncewith placebo (two-way crossover). Dosing days were separated by a 7-day washout. The effect of tolcapone on levodopa and 3-OMD pharmacokinetics was found to be similar with all levodopa/carbidopa formulations. The absorption of levodopa wasunaffected by tolcapone in all treatment groups and the maximum plasma concentration (C _max ) remained unchanged. When tolcapone was given with the immediate-release formulations, levodopa AUC increased by 60–90% and levodopa t _1/2 by 20–60%. With tolcapone and the controlled-release formulation, AUC increased by 80% and t _1/2 by 60%. With all levodopa/carbidopa formulations, 3-OMD C _max decreased by 80% and AUC by 70% with tolcapone. Thetolerability of all treatment combinations was similar. We conclude that adjunctive treatment with tolcapone should have similar levodopa-potentiating clinical effects, regardless of the levodopa/carbidopa formulation.     

The effect of an increased ratio of carbidopa to levodopa on the pharmacokinetics of levodopa

ABSTRACT – A randomized, cross-over study was designed to compare the effects of an increased ratio (from 1:10 to 1:4) of carbidopa to levodopa on the fate of levodopa and carbidopa in 11 healthy subjects. Four combinations of carbidopa/levodopa (10 mg/100 mg, 25 mg/100 mg, 25 mg/250 mg, 62.5/250 mg) were used. Plasma levodopa, carbidopa, dopamine and dopac concentrations as well as urinary excretions of levodopa and dopac were determined by a sensitive high-performance liquid chromatography with electrochemical detection after a single carbidopa/levodopa tablet. As the ratio of carbidopa to levodopa increased, there was a significant increase in apparent t_1/2 and AUC values of levodopa. At the same time the urinary excretion of levodopa increased and that of dopac decreased. The plasma ratios of levodopa/dopamine and levodopa/dopac and the urinary ratio of levodopa/dopac also increased. There were less subjective side-effects in the 1:4 groups than in the 1:10 groups. It is concluded that increasing the amount of carbidopa in relation to levodopa may be beneficial and further clinical studies are clearly indicated.     

No effect of chronic bromocriptine therapy on levodopa pharmacokinetics in patients with Parkinson's disease.

We studied the effect of chronic bromocriptine cotherapy on levodopa kinetics in seven patients with Parkinson's disease who were receiving levodopa therapy. Plasma levodopa concentrations were measured after a standard oral levodopa fasting dose over a 5-hour period, on two different sessions, without and with bromocriptine at a fixed daily dose of 15 mg. We found no statistically significant difference in the rate and extent of levodopa absorption between the two treatments, with minimal intrasubject variability. Our observations suggest that chronic bromocriptine cotherapy is unlikely to affect the plasma levodopa pharmacokinetics under standardized intake conditions or to contribute to a less predictable pattern of drug plasma concentrations.     

The influence of bromocriptine on the pharmacokinetics of levodopa in Parkinson's disease.

Several hypotheses have explained the beneficial effect of adding bromocriptine (BR) to levodopa (LD) in Parkinson's disease (PD) by interaction at the striatal level. In the present study we show the influence of BR on plasma LD values in an acute loading experiment (125 mg LD + 12.5 mg carbidopa [DCI] given alone and together with 2.5 mg BR at 0 time; 4 h observation). On the basis of this influence we have been able to differentiate between three groups of patients: (a) in six patients (five of them with frequent off episodes) LD values were significantly lower (p less than 0.05) when both drugs were given together (area under the curve [AUC] +/- SE 2.10 +/- 0.42 micrograms/ml/h vs. 4.96 +/- 1.10 micrograms/ml/h); (b) in eight patients (one with frequent akinesia) LD levels were significantly higher (p less than 0.003) when both drugs were given together (AUC +/- SE 4.05 +/- 0.51 micrograms/ml/h vs. 1.94 +/- 0.19 micrograms/ml/h); (c) in six patients (without motor fluctuations) no difference in LD levels was noted (AUC +/- SE 3.91 + 0.62 micrograms/ml/h vs. 3.81 +/- 0.70 micrograms/ml/h). The clinical evaluation (Webster scale) did not show substantial differences, except for increased dyskinesia, which correlated with higher LD levels. In summary, we suggest that the diminution of motor fluctuations and the occurrence of dyskinesias when BR is added to LD may stem from changes in LD plasma levels. These findings would be taken into consideration in the interpretation of therapeutic response fluctuations under combined treatment.     

A computational model of levodopa pharmacodynamics in Parkinson's disease.

A series of computational models were developed to better understand basal ganglia functions and the effects of levodopa pharmacodynamics in Parkinson's disease. The models employed a relatively new computational approach known as a neural network, which is a small number of simple processing units interconnected with designated constraints. A key difference from traditional computational modeling is that the networks are "trained" rather than programmed with experimental input and output data. After training, only a limited number of these models, could explain the pharmacodynamic data observed by Mouradian et al. in different groups of Parkinsonian patients. These successful models strongly argue for at least two pharmacologic mechanisms to explain the antiparkinsonian effect and dyskinesia tendency for the different classes of Parkinson's patients: never-treated, stable, wearing-off, and on-off. They suggest different roles for the striatal units by examining predictions of motor and dyskinesia tendency through theoretical blockade of each kind of unit. The models show that the antiparkinsonian effect in Parkinson's disease cannot be explained by the action of dopaminergic neurons on striatal neurons alone. Although the models necessarily oversimplify basal ganglia function, they provide a useful quantitative insight into how motor and dyskinesia behaviors may develop in different Parkinsonian subgroups.     

The effect of ascorbic acid on the pharmacokinetics of levodopa in elderly patients with Parkinson disease

Levodopa (LD) is one of the most effective drugs for clinical symptoms in patients with Parkinson disease (PD). Most PD patients are advanced in age and may have trouble with LD absorption because aging influences drug absorption processes. Previous reports have indicated that ascorbic acid (AsA) can reduce LD dosage without losing its effectiveness. The current study sought to determine whether AsA affects LD absorption in elderly PD patients. Sixty-seven elderly PD patients took a tablet orally containing 100 mg LD and 10 mg carbidopa following an overnight fast. Plasma LD concentrations were determined at 6 points up to 3 hours, using high-performance liquid chromatography with electrochemical detection. The area under the curve (AUC), peak drug concentration (Cmax), and time to peak drug concentration (Tmax) were calculated. The pharmacokinetic evaluation was repeatedly performed 1 week later in the same way except for adding 200 mg AsA to the tablet. The changes in AUC, Cmax, and Tmax between the tests were evaluated. Significant changes in these parameters were not observed when analyzed using data from all patients. However, significant increases in AUC and Cmax, and a significant reduction in Tmax by adding AsA were observed in 25 patients with baseline AUC < or =2500 ng.hour/mL. In conclusion, AsA can improve LD absorption in elderly PD patients with poor LD bioavailability. LD therapy in combination with AsA may be one of the strategies for PD treatment.     

Effect of long-term therapy on the pharmacodynamics of levodopa. Relation to on-off phenomenon.

To determine how the response to levodopa is altered by long-term therapy, we examined the dose response to 2-hour infusions of levodopa in three groups of parkinsonian patients: those who were previously untreated, those who exhibited stable responses, and those who exhibited fluctuating responses to levodopa therapy, using tapping speed as an index of bradykinesia. The baseline tapping speed was greater in the patients with stable responses than in the untreated patients, probably representing a "long-duration response" to levodopa therapy. A "short-duration response," indicated by an increase in tapping speed lasting hours, was observed in most patients in all groups. The onset of the short-duration effect was more rapid and the incremental increase in tapping speed was twice as large in the patients with fluctuating responses compared with the untreated patients and patients with stable responses. The duration of the short-duration effect was greatest in the untreated group but did not differ between the groups with stable and fluctuating responses. Dyskinesia was not observed in any of the de novo patients but was observed in three of 12 patients with stable responses and eight of nine patients with fluctuating responses to levodopa therapy. Dyskinesia appeared before or with the antiparkinsonian effects in patients with stable responses, giving no indication of a higher threshold for dyskinesia in these patients compared with those with fluctuating responses. The plasma half-life clearance, volume of distribution, and maximum plasma concentrations of levodopa did not differ among groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Acute effects of pulsatile levodopa administration on central dopamine pharmacodynamics

Inconsistencies in the response to individual levodopa doses occur in most patients with advanced Parkinson's disease (PD). To investigate the possible development of acute tachyphylaxis, we evaluated the effects of repeated injections of intravenous levodopa in 10 PD patients with motor fluctuations by administering, during a single day, a previously determined optimal levodopa dose repeatedly each time motor function returned to baseline. Peak antiparkinsonian response was lower by 20%, and peak plasma levodopa levels lower by 35% following the first dose compared with all subsequent doses. Neither peak dyskinesia scores nor the duration of motor response changed significantly with successive levodopa doses. These data suggest that pulsatile levodopa administration does not acutely alter dopamine receptor responsiveness, and that other pharmacokinetic and pharmacodynamic factors contribute to the dose-to-dose variability in response to levodopa.     

Levodopa: pharmacology, pharmacokinetics, and pharmacodynamics.

The success of L-dopa therapy in patients with Parkinson's disease and the concepts discussed in this article are summarized in Figure 6. Even in advanced stages of disease, 80% of parkinsonian disability remains responsive to L-dopa therapy. The 50% of the response contaminated by response fluctuations should be viewed, at least in part, as a hopeful sign that the system is still responding to L-dopa therapy. Unfortunately suboptimal control of response fluctuations is still a source of consternation for patient and treating physicians alike. Response fluctuations notwithstanding, it should be emphasized that patients actually do better at every stage of disease for having been on L-dopa, as recently confirmed in a retrospective study of the relationship between response fluctuations and the timing of initiation of therapy. To the extent that the increasing frequency, amplitude, and complexity of response fluctuations add to the overall parkinsonian disability, the phenomenon demands a better understanding that will hopefully lead to better corrective or preventive measures.     

Temporal relationships between plasma and cerebrospinal fluid pharmacokinetics of levodopa and clinical effect in Parkinson's disease.

We studied the pharmacokinetics of levodopa and its metabolites in plasma and ventricular cerebrospinal fluid in 4 parkinsonian patients with indwelling Ommaya reservoirs placed at the time of previous adrenal-medullary to caudate nucleus transplantation. Cerebrospinal fluid levodopa levels were 11.9% of those in plasma. Motor performance and dyskinesia correlated more closely with the time course of the appearance of levodopa in the ventricular cerebrospinal fluid than with the plasma levodopa concentration and did not correlate with plasma 3-O-methyldopa or cerebrospinal fluid 3-O-methyldopa or homovanillic acid. Our data confirm that the wearing off of the levodopa effect in patients with advanced Parkinson's disease is a function of drug concentration in the central nervous system.     

Gender differences in pharmacokinetics and pharmacodynamics of psychotropic medication.

OBJECTIVE: This review explores the theoretical background for and empirical evidence supporting gender-related differences in pharmacokinetics and pharmacodynamic properties of psychotropic medications. METHOD: The authors reviewed all English-language articles on this topic that involved original research using human subjects. RESULTS: Limited evidence suggests that young women seem to respond better to and require lower doses of antipsychotic agents and benzodiazepines than young men. The administration of exogenous hormones interacts with medications, changing plasma levels and possibly conferring greater risks for toxicity. Young women may have an enhanced response to nontricyclic antidepressants. CONCLUSIONS: Too little basic and clinical research has been conducted on sex differences in therapeutic effects and side effects of psychopharmacological treatments. Addressing these differences as well as similarities will lead to safer and more effective treatment for all patients.     

The experimental Alzheimer drug phenserine: preclinical pharmacokinetics and pharmacodynamics

Phenserine, a phenylcarbamate of physostigmine, is a new potent and highly selective acetylcholinesterase (AChE) inhibitor, with a >50-fold activity versus butyrylcholinesterase (BChE), in clinical trials for the treatment of Alzheimer's disease (AD). Compared to physostigmine and tacrine, it is less toxic and robustly enhances cognition in animal models. To determine the time-dependent effects of phenserine on cholinergic function, AChE activity, brain and plasma drug levels and brain extracellular acetylcholine (ACh) concentrations were measured in rats before and after phenserine administration. Additionally, its maximum tolerated dose, compared to physostigmine and tacrine, was determined. Following i.v. dosing, brain drug levels were 10-fold higher than those achieved in plasma, peaked within 5 min and rapidly declined with half-lives of 8.5 and 12.6 min, respectively. In contrast, a high (>70%) and long-lasting inhibition of AChE was achieved (half-life >8.25 h). A comparison between the time-dependent plasma AChE inhibition achieved after similar oral and i.v. doses provided an estimate of oral bioavailability of 100%. Striatal, in vivo microdialysis in conscious, freely-moving phenserine-treated rats demonstrated >3-fold rise in brain ACh levels. Phenserine thus is rapidly absorbed and cleared from the body, but produces a long-lasting stimulation of brain cholinergic function at well tolerated doses and hence has superior properties as a drug candidate for AD. It selectively inhibits AChE, minimizing potential BChE side effects. Its long duration of action, coupled with its short pharmacokinetic half-life, reduces dosing frequency, decreases body drug exposure and minimizes the dependence of drug action on the individual variations of drug metabolism commonly found in the elderly.     

Introduction to the pharmacokinetics and pharmacodynamics of benzodiazepines

1. 1. The contributions of pharmacokinetics and pharmacodynamics to the generation and maintenance of drug responses are reviewed from the literature.

2. 2. Potential pharmacokinetic determinants of duration of drug action are dose, lipid solubility and elimination half-life.

3. 3. Certain paradoxes are inherent in the view that clinical differences among benzodiazepines are due primarily to their elimination half-lives.

4. 4. It is concluded that the respective roles of pharmacokinetics and pharmacodynamics in the generation and maintenance of clinical responses to benzodiazepines require clarification.