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PubMed2001

Tolcapone increases plasma catecholamine levels in patients with Parkinson's disease.

Tolcapone is a catechol-ortho-methyl-tranferase (COMT) inhibitor that increases the L-DOPA half-life and the duration of effect in Parkinson's disease. We investigated the effect of tolcapone on the plasma catecholamine levels. We measured plasma catecholamines 2h after the first daily dose of L-DOPA or L-DOPA+tolcapone while resting and 2 and 10min after standing. We also measured the pharmacokinetics of L-DOPA and 3-OM-DOPA and the clinical response to the medication for 6h after the early morning dose. The levels of dopamine, norepinephrine, adrenaline and total catecholamines significantly increased and 3-OM-DOPA decreased with tolcapone. We did not observe significant changes in the plasma L-DOPA levels at the doses of tolcapone used in this study. Tolcapone side effects included worsening of dyskinesia and psychosis, diarrhea and elevation of liver enzymes. Twenty-four-hour ambulatory recording of arterial blood pressure and heart rate did not reveal cardiovascular side effects in patients treated with tolcapone for less than 1year. Since adrenergic stimulation may increase the hepatotoxic potential of commonly used drugs, usually thought of as safe for the liver, we postulate that some of the already reported life threatening complications of tolcapone could be related to excessive adrenergic stimulation by high catecholamine levels caused by inhibition of COMT activity.

Journal Article↗
PubMed2002

18F-dopa PET evidence that tolcapone acts as a central COMT inhibitor in Parkinson's disease.

Tolcapone is a potent, selective, and reversible inhibitor of cathecol-O-methyl-transferase (COMT). This enzyme plays a crucial role in the extraneural inactivation of catecholamine neurotransmitters. Tolcapone's ability to inhibit central COMT in humans at therapeutic concentrations is not yet clear. The aim was to determine the effect of tolcapone on central COMT activity in Parkinson's disease (PD) using (18)F-dopa positron emission tomography (PET). The study was a randomized two-way crossover study. Twelve PD patients were recruited. On the treatment days patients were given either tolcapone (200 mg) or placebo together with levodopa/carbidopa (100/125 mg) 1 h before the injection of (18)F-dopa. Data were acquired in 25 frames over 94 min for the first PET scan period. At the end of this period the patients were removed from the scanner for 90 min and subsequently repositioned and data acquired in six 10-min time frames over 60 min. Influx constants (Ki) were computed using a graphical approach with a plasma input function. Mean (18)F-dopa putamen Ki's for the first 30-90 min, primarily reflecting central dopa decarboxylase (DDC) activity, were similar in PD patients whether tolcapone was present (0.0078 +/- 0.0031 min(-1)) or absent (0.0078 +/- 0.0030 min(-1)). Mean putamen Ki values calculated 180-240 min after injection of (18)F-dopa, reflecting both central DDC and COMT activity, were unchanged from 30-90' values in the presence of tolcapone (0.0079 +/- 0.0030), implying blockade of central COMT, but were significantly reduced (0.0059 +/- 0.0028) in the absence of this drug. These findings are compatible with clinical doses of tolcapone having a significant blocking effect on peripheral and central COMT but not DDC activity in PD.

Aged↗
PubMed1997

Effects of tolcapone, a catechol-O-methyltransferase inhibitor, on motor symptoms and pharmacokinetics of levodopa in patients with Parkinson's disease.

The effects of tolcapone, a catechol-O-methyltransferase inhibitor, on the bioavailability and efficacy of levodopa were evaluated in 12 patients with Parkinson's disease (PD), 8 of whom showed signs of daily motor fluctuations (wearing-off phenomenon). Motor disabilities were assessed in 12 patients at 7 time points before and after the chronic administration of tolcapone using the Unified Parkinson's Disease Rating Scale (UPDRS). The UPDRS score was improved at all points of determination. Eight patients with wearing-off phenomenon on levodopa showed symptomatic improvement on the combination. The area under the curve (AUC) for levodopa increased by 34% (p = 0.0059) after the administration of tolcapone. The elimination half-life (T1/2) of levodopa was significantly prolonged by 81% (p = 0.0001) after the treatment. The AUC of 3-O-methyldopa, a metabolite of levodopa, was decreased by 79% (p = 0.0001) and the Cmax (maximum concentration) was also decreased by 80%d after the administration (p = 0.0001) of tolcapone. The combination of tolcapone and levodopa was well tolerated. Our findings suggest that tolcapone improves the pharmacokinetics of levodopa in plasma and motor symptoms of fluctuating PD patients. It is suggested that tolcapone may be useful drug adjunct to levodopa in treating patients with PD with wearing-off phenomena.

Aged↗
PubMed2001

Comparative toxicological study on the hepatic safety of entacapone and tolcapone in the rat.

Entacapone and tolcapone are novel COMT (catechol-O-methyltransferase) inhibitors indicated for the adjunctive treatment of Parkinson's disease (PD) in combination with levodopa. The marketing authorisation of tolcapone was suspended in the European Union (EU) in 1998 mainly due to severe abnormal hepatic reactions. This fact raised concern about the safety of COMT inhibitors in the treatment of parkinsonian patients. In order to investigate whether these COMT inhibitors exhibit different effects on the liver comparative toxicological studies were performed in the rat. Short term toxicological studies in rats at high oral doses of entacapone and tolcapone (200, 400 or 600mg/kg daily) were carried out. Tolcapone (400 mg/kg/day or 600 mg/kg/day) increased mortality after only one week treatment and induced signs of toxicity such as a rise in body temperature, stimulation of respiration and rapid onset of rigor mortis after death. Entacapone did not show any adverse effects at the tested dose levels. In the histopathological examination liver cell necrosis was observed in the tolcapone (400 and 600mg/kg/day) treated rats, but it revealed no treatment related signs of toxicity in entacapone-treated rats. We conclude that the toxicological profile of the two COMT inhibitors, entacapone and tolcapone, differ from each other, tolcapone--unlike entacapone--showed hepatotoxicity.

Animals↗
PubMed2002

Effects of entacapone and tolcapone on mitochondrial membrane potential.

Catechol-O-methyl transferase (COMT) inhibitors, entacapone and tolcapone, are used as an adjunctive treatment to L-dopa in Parkinson's disease. Based on their catechol structure, both inhibitors are potential uncoupling agents, but only tolcapone shows this effect in vitro at clinically relevant concentrations. This study was designed to evaluate the direct uncoupling effects of the two COMT inhibitors in vitro and in vivo. In isolated rat liver mitochondria, entacapone had no effect on the membrane potential at therapeutical concentrations, but both tolcapone and the reference compound 2,4-dinitrophenol disrupted the potential at low microM concentrations. Since protein binding is speculated to decrease the uncoupling effects in vivo, the COMT inhibitory effect of entacapone and tolcapone as a surrogate for the overall activity of these inhibitors was evaluated in vitro with or without serum. The COMT inhibitory activity of entacapone was reduced to half, while tolcapone had only about 1/10 of its activity left in the presence of serum. Further, uncoupling is known to induce an increase in the body temperature in vivo, and these effects were evaluated in the rat by a possible hyperthermic response to the treatment with entacapone or tolcapone in combination with L-dopa (10 mg/kg) and carbidopa (20 mg/kg). This combination with entacapone (400 mg/kg) had no effect on the rectal body temperature. In contrast, tolcapone (50 mg/kg) caused an elevation in the body temperature together with L-dopa and carbidopa (P < 0.01). Both in vitro and in vivo results indicate that entacapone does not impair energy metabolism related to uncoupling of oxidative phosphorylation.

Animals↗
PubMed2000

Population pharmacokinetics of tolcapone in parkinsonian patients in dose finding studies.

AIMS: To use pharmacostatistical models to characterize tolcapone's pharmacokinetics in parkinsonian patients, and to identify any demographic subpopulations which may be at risk of either under- or over-exposure to this catechol-O-methyltransferase (COMT) inhibitor. METHODS: Four hundred and twelve patients participated in three multicentre, parallel, double-blind, placebo-controlled, dose-finding studies and received either placebo or tolcapone (50, 200 or 400 mg three times daily) in addition to levodopa/decarboxylase inhibitor therapy. Sparse blood samples were obtained from 275 patients for tolcapone assay and the concentrations (1414 in total) were analysed using the NONMEM program. RESULTS: The pharmacokinetic model which best described the data was a two-compartment open model with first-order absorption and possibly a lag-time. Tolcapone pharmacokinetics were shown to be stable, with no systematic trend between 2 and 6 weeks of treatment. The absorption of the drug was shown to be rapid and concomitant food intake had only a minor effect on the relative bioavailability (10-20% reduction compared with fasting). The overall clearance of tolcapone could be estimated with good precision (approximately 4. 5-5 l h-1 ), and none of the investigated covariates (e.g. sex, age, body weight) had any clinically significant influence on this parameter. The volume of distribution showed relatively high variability and was calculated to be approximately 30 l, leading to an estimated half-life in patients of approximately 5-8 h. CONCLUSIONS: Using sparse concentrations and mixed effect-effects modelling analysis it is possible to describe the pharmacokinetics of tolcapone in parkinsonian populations. The parameter estimates obtained agreed with those obtained from conventional pharmacokinetic studies and no subpopulation was shown to be at risk of either under- or over-exposure to tolcapone.

Adult↗
PubMed1999

Microdialysis studies on the action of tolcapone on pharmacologically-elevated extracellular dopamine levels in conscious rats.

To elucidate the importance of catechol-O-methyltransferase, we performed striatal microdialysis studies in conscious rats given tolcapone, an inhibitor of catechol-O-methyltransferase, together with four compounds each of which elevates the extracellular dopamine content through a different mechanism. Tolcapone itself did not alter dopamine levels in the striatal microdialysis fluid but increased DOPAC and decreased homovanillic acid levels. However, tolcapone pretreatment (30 mg/kg) multiplied the already high dopamine levels after levodopa, and less so the moderately elevated dopamine levels after GBR-12909 (at 20 mg/kg) alone, but the minor (insignificant) dopamine-elevating effects of haloperidol and (+)-U232 were not altered. In all cases, a tolcapone pretreatment decreased homovanillic acid levels and elevated DOPAC levels. In further combination studies, GBR-12909 did not alter significantly the effects of levodopa/carbidopa on dopamine, DOPAC and homovanillic acid levels. In these rats, tolcapone enhanced the effect of GBR-12909 on extracellular dopamine but not on DOPAC. In conclusion, when levodopa and carbidopa are given together, COMT inhibition becomes extremely meaningful, and dopamine levels are multiplied by tolcapone. Otherwise, tolcapone is able to further elevate extracellular dopamine levels only when dopamine turnover is normal or low but not when it is high. Overall, the role of COMT in the elimination of synaptic dopamine remains minor compared to the dominance of the reuptake process.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2005

Tolcapone in Parkinson's disease: liver toxicity and clinical efficacy.

Parkinson's disease patients treated with a combination of levodopa and an aromatic L-amino acid decarboxylase inhibitor usually develop motor complications after some years. To minimise this problem, selective catechol-O-methyltransferase (COMT) inhibitors were developed in order to improve the poor pharmacokinetic profile of levodopa. Tolcapone and entacapone are the two marketed drugs in this class, and both increase the half-life of levodopa and improve clinical parameters, such as the increase in the duration of 'on' and decrease of 'off' time. Soon after its release, tolcapone was suspended in the EU due to it's implication in the deaths of three Parkinsonian patients. The cause of death in these patients was fulminant hepatitis. The mechanism by which tolcapone induces liver damage has been studied. Results show that this drug induces uncoupling of oxidative phosphorylation in mitochondria, thus significantly reducing the cell's capacity to generate ATP. This toxic effect was demonstrated both in vitro and in vivo in several models but the concentrations required to induce it are significantly higher than those needed to inhibit COMT. Inter-individual differences in the capacity to metabolise tolcapone may yield higher plasma levels and may explain its toxic effects in a small sample of patients. Recently, the suspension on tolcapone was lifted, based on new clinical data and ongoing monitoring of its use in other countries. The European Agency for the Evaluation of Medicinal Products concluded that, in some situations, tolcapone has a clinical efficacy that is superior to entacapone and that an adequate level of safety could be achieved with appropriate liver function monitoring and other measures. It is concluded that tolcapone can be safely used in Parkinsonian patients who do not respond or cannot, for other reasons, be prescribed with other COMT inhibitors.

Adenosine Triphosphate↗
PubMed2003

Tolcapone-related liver dysfunction: implications for use in Parkinson's disease therapy.

Levodopa is the cornerstone of idiopathic Parkinson's disease (PD) treatment. However, after long-term use of levodopa, a significant percentage of patients experience motor fluctuations, which worsen their quality of life. Catechol-O-methyltransferase (COMT) inhibitors reduce levodopa metabolism and enhance the respective plasma levels, resulting in improvements in symptoms and overall quality of life. Tolcapone was the first drug of this class to be marketed, but was withdrawn in the European Union due to its implication in the deaths of three PD patients due to hepatic failure. Three deaths from fulminant hepatic failure in 40000 patient-years is a number that is 10-100 times higher than the expected incidence in the general population and, according to the manufacturer's own information, the number is probably underestimated due to under-reporting of cases. In the US, tolcapone was not withdrawn, but restrictive liver enzyme monitoring measures were issued by authorities, which severely limited its use. No further deaths from hepatic failure were reported since these measures were implemented. The mechanisms by which tolcapone may induce liver toxicity are still under debate. It was thought that mitochondrial uncoupling of oxidative phosphorylation by tolcapone, and consequent impairment of energy production by hepatocytes, could be responsible for the observed effects. Some experts consider that the restrictive guidelines issued in the US regarding tolcapone use may be loosened with no consequential reductions in safety. It was suggested that ongoing clinical information about safety should be considered and periodical revisions of the restrictions made accordingly. The identification of the molecular and biochemical basis of tolcapone hepatotoxicity, when completed, should also provide important indications for the clinical use of this drug. In conclusion, appropriate monitoring of liver function can ensure adequate safety in PD patients receiving tolcapone, who can therefore benefit from the symptomatic improvements obtained with this drug.

Antiparkinson Agents↗
PubMed1997

Studies on the tight-binding nature of tolcapone inhibition of soluble and membrane-bound rat brain catechol-O-methyltransferase.

Catechol-O-methyltransferase (COMT) is an enzyme that plays an important role in the inactivation of catecholamine neurotransmitters. Experimental and clinical data suggest that COMT inhibitors may be useful in Parkinsonian patients. Among COMT inhibitors, nitrocatechol derivatives are the most potent and selective. In this study, we evaluated the kinetics of rat brain COMT, as well as its mechanisms of inhibition by tolcapone. Rat whole-brain homogenates and the corresponding soluble and membrane-bound fractions were evaluated for their epinephrine 3-O-methylating activity. Tolcapone exhibited a very low IC50 in all the three enzyme preparations. In whole-brain homogenates, saturation curves made in the presence of 1 nM tolcapone displayed, when compared with controls, a reduction in Vmax without changes in Km, which suggested a noncompetitive type of inhibition. This was confirmed by experiments in which the IC50 value for tolcapone was not affected by substrate concentration. Nevertheless, this classic kinetic analysis is not suitable for a tight-binding inhibitor. A very low IC50, an inhibition potency that is dependent on the previous contact time of the inhibitor with the enzyme and an enzyme titrating capacity were the three criteria that tolcapone met as a tight-binding inhibitor in the rat brain. In conclusion, our results show that tolcapone is a highly potent tight-binding inhibitor of brain soluble and membrane-bound COMT, but because of difficulties in determining the type of inhibition for this type of compound, we cannot confirm previous claims about the competitive type of COMT inhibition produced by tolcapone.

Animals↗
PubMed2002

Different modes of action of catecholamine-O-methyltransferase inhibitors entacapone and tolcapone on adenylyl cyclase activity in vitro.

Catechol-O-methyltransferase (COMT) inhibitors such as entacapone and tolcapone are used as adjuncts to L-DOPA ( l-3,4-dihydroxyphenylalanine, levodopa) in the treatment of Parkinson's disease. Tolcapone has been reported to associate with diarrhoea, a common reason for study withdrawal. The mechanism of this adverse effect is not yet understood. Cholera toxin causes diarrhoea by permanent activation of G(s) proteins, resulting in increased adenylyl cyclase (AC) activity. The aim of this study was to examine the effects of the COMT inhibitors entacapone and tolcapone on AC activity in membranes isolated from rat striatum, a brain structure enriched with dopaminergic G-protein-coupled receptors and AC activity. This study demonstrates differential effects of tolcapone and entacapone on Gpp(NH)p/dopamine-stimulated AC activity. Entacapone enhanced the stimulatory effect of Gpp(NH)p/dopamine, whereas tolcapone attentuated this effect, suggesting that diarrhoea associated with tolcapone treatment is not caused by permanent activation of G(s) proteins.

Adenylyl Cyclase Inhibitors↗
PubMed2004

Differences in toxicity of the catechol-O-methyl transferase inhibitors, tolcapone and entacapone to cultured human neuroblastoma cells.

Tolcapone and entacapone are catechol-O-methyltransferase (COMT) inhibitors used as adjuncts to levodopa in the treatment of Parkinson's disease (PD). The use of tolcapone has been limited by its hepatotoxicity, the cause of which remains uncertain. Tolcapone compound is an uncoupler of mitochondrial respiration in isolated mitochondria and this action may be relevant to its effect on liver function. We have examined the actions of COMT inhibitors on cultured cells, comparing them with those of the classical uncoupler carbonyl cyanide p-(trifluoromethoxy) phenylhydrazone (FCCP), in order to provide insight into their mechanism of potential toxicity. Tolcapone and FCCP were shown to be toxic to human neuroblastoma SH-SY5Y cells and caused a profound reduction in ATP synthesis. Entacapone was not toxic to SH-SY5Y. Tolcapone and FCCP were shown to be equally toxic to cells depleted of mtDNA and thus devoid of a functional respiratory chain. This study demonstrates that tolcapone markedly inhibits ATP synthesis in cultured cells mirroring the effects of a classical uncoupler. However its toxicity may also involve a mechanism independent of its effects upon oxidative phosphorylation.

Benzophenones↗
PubMed1997

Catechol O-methyltransferase inhibitor tolcapone has minor influence on performance in experimental memory models in rats.

Two catechol O-methyltransferase inhibitors, peripherally acting entacapone and also centrally acting tolcapone, were tested regarding their capacity to influence learning and memory in adult intact rats. Tolcapone was also studied in rats treated with scopolamine, in adult rats lesioned in the nuclei basalis magnocellularis, and in aged rats. Spatial working memory performance (radial-arm maze) of intact rats was facilitated following pretraining i.p. administration of tolcapone (10 mg/kg). Entacapone was ineffective at doses of 10 and 30 mg/kg. Senescent poor performers improved their accomplishment in the spatial memory task (linear-arm maze) under the influence of tolcapone. Scopolamine (1 mg/kg) impaired working memory performance. Bilateral lesions in the nucleus basalis magnocellularis reduced choline acetyltransferase activity in the frontal cortex by 26% and retarded the learning rate of spatial place task. Tolcapone was not able to counteract the performance deficits in these models. It is concluded that tolcapone can either slightly improve or impair the memory functions depending on task specific elements and performance factors.

Aging↗
PubMed1999

Metabolism and excretion of tolcapone, a novel inhibitor of catechol-O-methyltransferase.

AIMS: To investigate the rate of excretion and routes of metabolism of tolcapone, a novel inhibitor of catechol-O-methyltransferase (COMT). METHODS: Six healthy male volunteers were given 200 mg [14C]-tolcapone (approximately 50 muCi) orally. To assess excretion balance and to identify metabolites, urine and faeces were collected before administration and until radioactivity fell below 75 d min-1 ml-1 (urine) and 100 d min-1 mg-1 (faeces). Blood samples were collected frequently before and after administration to determine plasma radioactivity, to identify tolcapone metabolites and to measure plasma tolcapone and its methylated derivative 3-O-methyltolcapone (3-OMT). RESULTS: The mean proportion of the dose excreted in urine was 57.3% and in faeces 40.5%. Excretion was almost complete (more than 95%) in all participants after 9 days. The major early metabolite present in plasma was the 3-O-beta, d-glucuronide conjugate, which was detectable within 2 h after dosing. The major late metabolite in plasma was 3-OMT. The 3-O-beta, d-glucuronide was also the most abundant metabolite in urine and faeces, accounting for 27% and 33%, respectively, of the total radioactivity excreted by these routes and for 26% of the original dose. Reduction of the nitro moiety yields an amine derivative, detected in both urine and faeces, with subsequent modifications, such as acetylation of the amine group and conjugation with glucuronic acid or sulphate, or both. Oxidative reactions due to cytochrome P450 enzymes are of small significance, as is 3-O-methylation by COMT. CONCLUSIONS: Tolcapone is almost completely metabolized and excreted in urine and faeces (only 0.5% of tolcapone was excreted unchanged); glucuronidation is the most important route of metabolism. The relatively long duration of excretion is caused by the long half-life of 3-OMT.

Adult↗
PubMed2000

Population pharmacokinetics of levodopa in patients with Parkinson's disease treated with tolcapone.

OBJECTIVE: To use pharmacostatistical models to evaluate the overall exposure of patients with Parkinson's disease to levodopa in the presence and absence of tolcapone. METHODS: Four hundred twelve patients with Parkinson's disease with fluctuating and nonfluctuating responses to levodopa participated in three multicentered, parallel, double-blind, placebo-controlled dose-finding studies and received either placebo or tolcapone in addition to levodopa-decarboxylase inhibitor therapy. Sparse blood samples were obtained from 393 patients for levodopa and 3-O-methyldopa assay, and the data were analyzed with use of the NONMEM program. RESULTS: The fraction of levodopa metabolized to 3-O-methyldopa was substantially reduced by the co-administration of tolcapone (by 65%, 74%, and 84% with tolcapone doses of 50, 200, and 400 mg, respectively, in fluctuators, and by 50% and 90% with doses of 200 and 400 mg, respectively, in nonfluctuators). This led to an overall reduction in levodopa clearance (CL) of approximately 15% to 25% in fluctuators and 20% to 30% in nonfluctuators. Because this was partly compensated for by a reduction in levodopa dose in these studies, the total daily exposure of patients to levodopa was only slightly increased (11% to 16%). The peak-trough fluctuations of plasma levodopa (Cmax-Cmin) were reduced in both populations in a dose-dependent fashion. CONCLUSIONS: Tolcapone effectively inhibited the formation of 3-O-methyldopa and resulted in a decrease in levodopa CL. The consequent increase in levodopa bioavailability was mostly offset by reductions in levodopa dose. It is possible that decreased fluctuations in plasma levodopa concentrations rather than increased levodopa exposure may explain the clinical benefits obtained with tolcapone.

Adult↗
PubMed1995

Acute administration of levodopa-benserazide and tolcapone, a COMT inhibitor, Parkinson's disease.

Tolcapone, a catechol-O-methyltransferase inhibitor, can interfere with the metabolism of levodopa and dopamine and could prolong the motor effect induced by levodopa in parkinsonian patients. To test this hypothesis, we studied the motor effect induced by three acute administrations of a dose of levodopa-benserazide (Madopar) with either 200 mg or 400 mg of tolcapone or placebo, in a double-blind latin-square design. The duration of the on-phase could be compared in 10 parkinsonian patients suffering from square-shaped motor effect. In comparison to placebo, 200 mg and 400 mg of tolcapone significantly increased the mean duration of the on-phase by 61.7 min ( +/- 19.4 SEM) and by 72.2 min ( +/- 18.5), respectively. This clinical effect is suggested to be related mainly to the increase in levodopa area under the curve and half-life induced by tolcapone. The intensity in dyskinesias was increased by 400 mg of tolcapone. Tolcapone appears to be well tolerated and could be helpful as an adjuvant treatment to levodopa in parkinsonian patients with motor fluctuations.

Aged↗
PubMedDate not supplied

The relationship between COMT genotype and the clinical effectiveness of tolcapone, a COMT inhibitor, in patients with Parkinson's disease.

Patients with Parkinson's Disease (PD) have a variable response to tolcapone, a catechol-O-methyltransferase (COMT) inhibitor. In addition, a subset of patients develop severe diarrhea as a side effect. Two codominant alleles for the COMT gene exist, coding for low and high activity, resulting in low-, medium-, and high-activity genotypes. This study investigates the relationship between this variation in genotype and clinical effects in patients with PD taking tolcapone. To investigate the relationship between COMT polymorphism and clinical response, 24 patients who completed tolcapone clinical trials provided blood samples for COMT genotype analysis. Change in levodopa dose and United Parkinson Disease Rating Scale (UPDRS) Part III (motor subscale) were analyzed at baseline, at 1-2 weeks, and 6 months after initiation of tolcapone. Genotype analysis was performed on seven patients who had diarrhea as a side effect. There was no significant correlation between genotype and improvement in UPDRS score (p = 0.29) according to a linear models approach that adjusted for the subject's severity of PD, tolcapone dose (either 100 or 200 mg three times daily) and initial differences in baseline scores. No significant difference was seen in change in daily levodopa intake and genotype. There was also no relation between diarrhea and COMT genotype. These results indicate that, in the treatment of Parkinson's disease, COMT genotype is not a major contributor to the clinical response to tolcapone.

Aged↗
PubMed1995

Pharmacokinetic-pharmacodynamic interaction between the COMT inhibitor tolcapone and single-dose levodopa.

1. Single oral doses of the catechol-O-methyltransferase (COMT) inhibitor tolcapone (10-800 mg) or placebo were administered simultaneously with a dose of levodopa/benserazide 100/25 mg to seven sequential groups of six healthy male subjects in a two-way crossover study. 2. Plasma concentrations of tolcapone, its metabolite 3-O-methyltolcapone, levodopa and 3-O-methyldopa (3-OMD) were determined in conjunction with COMT activity in erythrocytes. 3. The drug combination was well tolerated at all dose levels and there were no signs indicative of an increase in dopaminergic stimulation. 4. Tolcapone caused a rapid and reversible inhibition of COMT activity in erythrocytes in parallel with a dose-dependent decrease in the formation of 3-OMD. Tolcapone increased the area under the concentration-time curve and elimination half-life of levodopa. The maximum effects were obtained at a dose of about 200 mg when both parameters increased approximately twofold. The drug had no influence on the maximum concentration of levodopa. 5. Tolcapone was rapidly absorbed and eliminated with, on average, a tmax of 1.5 h and a t1/2 of 2.3 h. The drug showed dose-proportional pharmacokinetics, in contrast to 3-O-methyltolcapone whose formation was relatively decreased at higher doses. 6. Plasma concentrations of tolcapone correlated with inhibition of COMT activity in erythrocytes and suppression of 3-OMD levels, but not with changes in levodopa pharmacokinetics.

Adult↗