Disease relevance of Tolcapone

• Tolcapone and neurotoxicity in Parkinson's disease [1].
• Dyskinesia developed or worsened in 18% of patients receiving placebo, in 51% receiving tolcapone 100 mg tid, and in 64% receiving 200 mg tid, with most cases occurring within the first 30 days of the study [2].
• Tolcapone must also be monitored for possible liver dysfunction [3].
• Post-marketing surveillance studies noted 3 instances of acute liver failure with death after 60,000 patients had received tolcapone for a total of 40,000 patient-years [4].
• Tolcapone appears to be beneficial in the treatment of patients with parkinsonism who have not yet developed motor fluctuations [5].

Psychiatry related information on Tolcapone

• Repeated administration of tolcapone, an inhibitor of catechol-O-methyltransferase, was able to partially restore the memory deficits caused by bilateral cholinotoxin (AF64A) lesions in the basal magnocellular nuclei of Meynert [6].
• In this paper we extend the psychometric assessment of PIMS to a new set of patients, in the context of a cross-over trial by Hoffman-La Roche Ltd, comparing two doses of tolcapone in 116 PD patients who had developed wearing off effect on levodopa [7].

High impact information on Tolcapone

• The COMT activity of recombinant protein was inhibited competitively (IC50 = 700 nM) by the selective COMT inhibitor Ro 40-7592 [8].
• 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 [9].
• Population pharmacokinetics of levodopa in patients with Parkinson's disease treated with tolcapone [9].
• Two basic classes of COMT inhibitors are being studied in patients with PD: those that act exclusively extracerebrally or peripherally (e.g., entacapone) and those that cross the blood-brain barrier (e.g., tolcapone) [10].
• CONCLUSIONS: Half of the recommended dosage of tolcapone should be administered to patients with cirrhosis of the liver to maintain the target steady-state concentration of unbound drug and to avoid accumulation of tolcapone glucuronide [11].

Chemical compound and disease context of Tolcapone

• This multicenter, double-blind, placebo-controlled study used two 10-hour clinical evaluations to compare the efficacy and safety of three doses of tolcapone (50, 200, and 400 mg tid) with placebo in patients with Parkinson's disease (PD) experiencing motor fluctuations from levodopa/carbidopa [12].
• Differences in toxicity of the catechol-O-methyl transferase inhibitors, tolcapone and entacapone to cultured human neuroblastoma cells [13].
• The influence of tolcapone, an inhibitor of catechol-O-methyl transferase, was evaluated on the disposition of apomorphine, a dopamine agonist used to treat Parkinson's disease, to explain a previously observed increase of duration of the effect of apomorphine associated with tolcapone [14].
• A pilot evaluation of the tolerability, safety, and efficacy of tolcapone alone and in combination with oral selegiline in untreated Parkinson's disease patients. Tolcapone De Novo Study Group [15].
• Although the increase was more pronounced when tolcapone was combined with 50 mg benserazide, the levels were still substantially lower than concentrations causing toxicity in animals [16].

Biological context of Tolcapone

• Effect of liver impairment on the pharmacokinetics of tolcapone and its metabolites [11].
• Tolcapone concentration-dependently inhibited COMT activity in erythrocytes and exhibited dose-proportional kinetics [17].
• These results show that tolcapone can increase plasma apomorphine bioavailability by modifying its liver catabolism [14].
• With tolcapone and the controlled-release formulation, AUC increased by 80% and t1/2 by 60% [18].
• In contrast, tolcapone (50 mg/kg) caused an elevation in the body temperature together with L-dopa and carbidopa (P < 0.01) [19].

Anatomical context of Tolcapone

• Tolcapone caused a rapid and reversible inhibition of COMT activity in erythrocytes [17].
• We administered Ro 40-7592, an inhibitor of the enzyme catechol-O-methyltransferase (COMT) that crosses the blood-brain barrier, to rats and monitored extracellular catecholamine levels in the corpus striatum before and after the intraperitoneal administration of a bolus of l-dopa [20].
• Cerebrospinal fluid 3,4-dihydroxyphenylacetic acid level after tolcapone administration as an indicator of nigrostriatal degeneration [21].
• Tolcapone compound is an uncoupler of mitochondrial respiration in isolated mitochondria and this action may be relevant to its effect on liver function [13].
• This study demonstrates that tolcapone markedly inhibits ATP synthesis in cultured cells mirroring the effects of a classical uncoupler [13].

Associations of Tolcapone with other chemical compounds

• Optimizing levodopa pharmacokinetics with multiple tolcapone doses in the elderly [22].
• Assessments included tolerability, pharmacokinetics of tolcapone, levodopa, and 3-O-methyldopa, and inhibition of COMT activity in erythrocytes [22].
• METHODS: Adult male Wistar rats were treated with a nitrocatechol COMT inhibitor (entacapone, tolcapone, or nitecapone, 30 mg/kg, orally), and the urinary excretion of dopamine and sodium was quantitated [23].
• Inhibition of monoamine oxidases (MAOs) by pargyline, but not of catechol-O-methyltransferase (COMT) by tolcapone, slowed down DA elimination in knockout mice [24].
• Treatment with tolcapone decreased the catalytic activity of methionine adenosyltransferase (MAT) (from 15.4 +/- 1.6 to 11.3 +/- 1.4 pmol mg-1 min-1, p < 0.0001) while phenelzine treatment had no significant effect [25].

Gene context of Tolcapone

• These provisional findings suggest that newly developed COMT inhibitors such as tolcapone, applied in Parkinson's disease, might in due time be considered in the treatment of ADHD [26].
• Entacapone showed a 3 to 4 times higher V(max) value and a 4 to 6 times lower K(m) value compared with those of tolcapone both in UGT1A9 cell lysates and in human liver microsomes [27].
• 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)) [28].
• Michaelis-Menten parameters were determined for entacapone and tolcapone using recombinant human UGT isoforms and human liver microsomes to compare the kinetic properties of the two COMT inhibitors [27].
• Tolcapone (T) is a novel catechol-O-methyltransferase (COMT) inhibitor recently introduced for the treatment of Parkinson's disease [29].

Analytical, diagnostic and therapeutic context of Tolcapone

• However, in clinical trials of tolcapone, liver chemistry tests were elevated more than 3 times above the upper limit of normal in approximately 1% of patients who took the 100 mg dose and in approximately 3% of patients who took the 200 mg dose [4].
• With 200 mg tolcapone tid, unified Parkinson's disease rating scale motor and total scores were significantly reduced, and quality of life (sickness impact profile) scores were significantly improved [30].
• STUDY DESIGN: In an open, two-way crossover study, 16 patients with moderate liver disease (eight with cirrhotic and eight with noncirrhotic liver disease) and eight healthy subjects received an oral dose of 200 mg tolcapone and an intravenous dose of 50 mg tolcapone on separate occasions [11].
• Oral administration of the COMT inhibitor tolcapone (2 doses of 15 mg/kg each with a 4-h interval) significantly reduced enzyme activity in the monkey brain [21].
• In vivo brain microdialysis was used to assess the effects of tolcapone, a novel central and peripheral inhibitor of catechol-O-methyltransferase on striatal 3,4-dihydroxyphenyl-L-alanine (L-dopa) and dopamine metabolism [31].

References