Tolcapone (Ro 40-7592), like entacapone, is rapidly absorbed after oral administration; in contrast to entacapone, it reaches Tmax in approximately 1.5 to 2 hours (18,89,90). The bioavailability of an oral dose is about 60% (91). Tolcapone is very highly (99.9%) protein bound (92). Metabolism of tolcapone is primarily, but not exclusively, via glucuronidation (93) since both methylation and oxidation also occur (94). The elimination T1/2 of tolcapone is between two and three hours, which is distinctly longer than that of entacapone (89). At doses above 200 mg three times a day (TID), some accumulation of tolcapone can occur, but this appears to be of no real practical significance since levels, even at doses of 800 mg TID, remain well below those associated with toxicity in animals (89).
Unlike entacapone, tolcapone is sufficiently lipophilic to cross the blood-brain barrier, to some degree (95). Tolcapone-induced inhibition of COMT within the brain has been demonstrated in animal experiments (94,96). In primates, where administered tolcapone doses were within the therapeutic range, COMT activity within the cerebellum was reduced by 60% (97). It has been less convincingly demonstrated that similar central COMT inhibition takes place in humans receiving tolcapone in clinically relevant doses. However, fluorodopa positron emission tomography (PET) studies have provided some evidence that such central COMT inhibition does take place with tolcapone doses of 200 mg (98). Tolcapone has also been identified in the cerebrospinal fluid (CSF) of patients with PD one to four hours after oral intake of 200 mg of tolcapone in concentrations sufficient to reduce CSF COMT activity by 75% (99). Inhibition of COMT within both peripheral and CNS structures provides some theoretical advantages over peripheral inhibition alone since, in addition to the peripheral levodopa-sparing capability, concomitant central COMT inhibition would not only reduce metabolism of levodopa to 3-OMD within the striatum, but would also block one route of the metabolism of dopamine itself.
Single dose studies demonstrated tolcapone to be a noticeably more potent COMT inhibitor than entacapone. At a dose of 200 mg, tolcapone increases the levodopa AUC from 50% to 100%, prolongs the levodopa T1/2 by 60% to 80%, and reduces the AUC of 3-OMD by 64% (18,50,100,101). No appreciable increase in the levodopa C or T is seen at this dose of tolcapone, although some delay in the T becomes max max r ' o J max evident at higher doses (100).
A number of double-blind, placebo-controlled clinical trials have confirmed the efficacy of tolcapone in reducing motor fluctuations in individuals with PD (102-105). In each of these multicenter trials, which varied in length from six weeks to six months, significant increases in "on" time and reductions in "off" time were documented in the tolcapone-treated groups, compared with the placebo groups. Reduction in both total daily levodopa dosage and number of levodopa doses taken was often evident in the tolcapone-treated groups.
In these four multicenter studies, in which 517 patients (out of 745 enrolled) received tolcapone in various doses ranging from 50 to 400 mg TID, adverse effects were generally mild and most often dopaminergic in character (102-105). In the three studies, where the treatment groups consisted of placebo versus 100 mg TID versus 200 mg TID, dyskinesia was reported as an adverse event in 19% to 21%, 37% to 62%, and 53% to 66%, respectively (103-105). Tolcapone has been compared favorably with two dopamine agonists, bromocriptine and pergolide, in clinical trials (106,107), although these trials were open-label and possibly underpowered (108).
Diarrhea, at times unresponsive to medication and of sufficient severity to warrant drug discontinuation, was reported in a small percentage of individuals receiving tolcapone, possibly in a dose-related pattern (50,104,105). The mechanism of the diarrhea is uncertain, although tolcapone has been noted to trigger intestinal fluid and electrolyte secretion, albeit not the actual diarrhea, in dogs (18,109). As with entacapone, yellow/orange urine discoloration also occurred in some individuals.
In the initial multicenter trials, elevation of liver transaminase levels occurred in a small number of individuals, but all were clinically asymptomatic and the laboratory abnormalities sometimes returned to normal, despite continued treatment.
In all clinical trials of tolcapone the reported incidence of transaminase elevations greater than three times the upper limit of normal was approximately 1% at a dose of 100 mg TID and 3% at a dose of 200 mg TID (110). However, following introduction of tolcapone into routine clinical use, three cases of fulminant hepatic failure with a fatal outcome occurred, which led regulatory agencies in Europe and Canada to withdraw tolcapone from the market, and the Food and Drug Administration in the United States to severely limit its use to situations where other drugs had not provided sufficient benefit (111). No further deaths have been reported and recently these restrictions have been relaxed. Tolcapone can once again be used in Europe, with appropriate monitoring of liver function, in persons with symptom fluctuations receiving levodopa who cannot tolerate or have not responded to other COMT inhibitors (112). A report from the Quality Standards Subcommittee of the American Academy of Neurology also provides similar guidelines for tolcapone use (113). Baseline liver function tests must be normal and the monitoring of liver function must be performed on a regular basis (every two to four weeks for the first six months and thereafter as clinically necessary) in patients receiving tolcapone (113).
The mechanism of tolcapone-induced hepatotoxicity is not entirely clear. Uncoupling of oxidative phosphorylation in mitochondria (112,114,115), perhaps mediated by oxidation of tolcapone metabolites to reactive intermediates (116), has been suggested. Tolcapone may also provoke cellular damage by a mechanism independent of its effects on oxidative phosphorylation, perhaps by opening the mito-chondrial permeability transition pore, with consequent apoptotic cell death (115).
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