A Tolcapone

Entacapone is indicated in combination with lev-odopa in patients with motility fluctuations (more than 1 hour gain in the 9-10 hour on phase). Marketing approval was awarded for entacapone just after tolcapone, a central and peripheral COMTI, was withdrawn from the market because of fulminant hepatitis. 

Da Prada M, Borgulya J, Napolitano A, Ziircher G. Improved theraphy of parkinson s disease with tolcapone, a central and peripheral COMT inhibitor with an S- adenosyl-L-methionine-sparing effect. Clinical Neuropharmacology 1994 17 26-37. 

Micek ST, Ernst ME. Tolcapone a novel approach to Parkinson s disease. Am J Health Syst Pharm 1999 56(21) 2195-205. 

Table 3 lists the dose and incidence of the hepatotoxicity for various drugs, some of which have been withdrawn as a result of these findings. Some of the drugs show effects on liver function earlier than the actual onset of liver toxicity, with serum aminotransferase levels raised by threefold the upper limit of normal (ULN). The incidence of this is much higher and can show a classical dose response for instance, tolcapone, a catechol-O-methyltransferase inhibitor used as an adjunct to levodopa in Parkinson s disease, produces threefold the ULN in 1-3% of patients receiving 100 mg TID and 3.7% of patients receiving 200 mg TID (Olanow and Watkins 2007). Tolcapone, an o-nitrocatechol, is metabohzed to reactive intermediates - o-quinone or quinoneimine species - by human fiver microsomes (Smith et al. 2003). 

Lave, T. Dupin, S. Schmitt, M. Kapps, M. Meyer, J. Morgenroth, B. Chou, R.C. Jaeck, D. Coas-solo, P. Interspecies scaling of tolcapone, a new inhibitor of catechol-O-methyltransferase (COMT). Use of in vitro data from hepatocytes to predict metabolic clearance in animals and humans, Xenobiotica, 1996, 26, 839-851. 

Clinical studies, available only for entacapone and tolcapone, support preclinical findings. A dose-dependent (100-800 mg) inhibition of the COMT activity of the erythrocytes can be seen after nitrocatechols. However, effective and sufficient dose levels of both entacapone and tolcapone, given concomitantly with L-dopa and DDC inhibitors to patients with Parkinson s disease, appear to be 100-200 mg. However, the treatment strategies of entacapone and tolcapone differ entacapone is a short-acting compound that is given with each dose of L-dopa, and COMT activity may even... 

A newer classification of antiparkinson drugs is the catechol-O-methyltransferase (COMT) inhibitors. Examples of the COMT inhibitors are entacapone (Comtan) and tolcapone (Tasmar). 

The COMT inhibitors are used as adjuncts to levodopa7 carbidopa in Fhrkinson s disease Tolcapone is a potent COMT inhibitor that easily crosses the blood-brain barrier. However, the drug is associated with liver damage... 

The adverse reactions most often associated with the administration of the COMT inhibitors include disorientation, confusion, light-headedness, dizziness, dyskinesias, hyperkinesias, nausea, vomiting, hallucinations, and fever. Other adverse reactions are orthostatic hypotension, sleep disorders, excessive dreaming, somnolence, and muscle cramps. A serious and possibly fatal adverse reaction that can occur with the administration of tolcapone is liver failure... 

These dm are contraindicated in patients with a hypersensitivity to the dragp and during pregnancy (Category C) and lactation. Tolcapone is contraindicated in patients with liver dysfunction. The COMT inhibitors are used with caution in patients with hypertension, hypotension, and decreased hepatic or renal function. 

A serious and potentially fatal adverse reaction to tolcapone ishepatic injury. Regular blood testing to monitor liver function is usually prescribed. The phys dan may order testing of serum transaminase levels at frequent intervals(eg, every 2 weeks for the first year and every 8 weeks thereafter). Treatment is discontinued if the ALT (SOFT) exceeds the upper normal limit or sgns or symptoms of liver failure develop. 

It is generally aeeepted that COMT is an extraeellular enzyme in the CNS that catalyses the transfer of methyl groups from S-adenylmethionine to the meta-hydroxy group of the eateehol nueleus. Until recently the only inhibitors of this enzyme were pyragallol and eateehol whieh were too toxic for clinical use. Now other inhibitors have been developed, e.g. entaeapone and tolcapone, but these are used mainly to protect dopa (also a catecholamine) from O-methylation, in the treatment of Parkinson s disease (Chapter 15). 

There is also some evidence for subtypes of COMT but this has not yet been exploited pharmacologically. Certainly, the majority of COMT is found as soluble enzyme in the cell cytosol but a small proportion of neuronal enzyme appears to be membrane bound. The functional distinction between these different sources of COMT is unknown. COMT inhibitors also exist (e.g. pyrogallol), mostly as catechol derivatives, but so far, most have proved to be highly toxic. Only recently have drugs been developed which are selective for COMT one of these agents, tolcapone, is used currently in treatment of Parkinson s disease (see Chapter 15). 

Because entacapone has a shorter half-life, 200 mg is given with each dose of carbidopa/L-dopa up to eight times a day. Dopaminergic adverse effects may occur and are managed easily by reducing the carbidopa/L-dopa dose. Brownish-orange urine discoloration may occur (as with tolcapone), but there is no evidence of hepatotoxicity from entacapone. 

A final pharmacological strategy for treatment of Parkinson s disease comes from enzyme inhibition. This was initally done with an MAO inhibitor, L-deprenyl (selegiline, Eldepryl), but more recent drugs have become available that are COMT inhibitors. L-Deprenyl is an inhibitor of MAOB, which is the form of MAO selective to dopamine. Thus, it may increase the amount of available dopamine for release. Second, it may protect dopamine neurons by reducing the oxidative stress concomitant with dopamine metabolism (Olanow 1997). Third, L-deprenyl is metabolized into amphetamine and methamphetamine, which may contribute to their antiparkinsonian effects. Unlike other treatments for Parkinson s disease, L-deprenyl seems to slow the progression of the disease. Tolcapone (Tasmar) is a COMT inhibitor, which prevents extracellular breakdown of dopamine. 

For many of the drugs associated with hepatotoxicity, there are examples of structurally related drugs which are latent to bioactivation and toxicity because of the absence of the toxicophore or the existence of alternate metabolic pathways. For example, the hepatotoxicity associated with the use of the anti-Parkinson s agent tolcapone does not occur with the structurally related drug entacapone, despite administration at doses similar to tolcapone (200-1000 mg QD). This disparity may be explained in part by the observation that entacapone does not succumb to the bioactivation reactions of tolcapone in humans (Scheme 15.3) [35]. It is also noteworthy that tolcapone but not entacapone is a potent uncoupler of oxidative... 

Combined with levodopa and a decarboxylase inhibitor more stable levodopa levels can be obtained. Tolcapon has been withdrawn in many countries because of serious liverfunction disturbances, rhab-domyolysis and neuroleptic malignant syndrome. 

Adjunctive treatment of Parkinson s disease PO Initially, 100-200 mg 3 times a day concomitantly with each dose of carbidopa and levodopa. Maximum 600 mg/day Dosage in hepatic impairment Patients with moderate to severe cirrhosis should not receive more than 200 mg tolcapone 3 times a day... 

Assal F, Spahr L, Hadengue A, et al. Tolcapone and fulminant hepatitis. Lancet 1998 352 958. 

The pharmacologic effects of tolcapone and entacapone are similar, and both are rapidly absorbed, bound to plasma proteins, and metabolized before excretion. However, tolcapone has both central and peripheral effects, whereas the effect of entacapone is peripheral. The half-life of both drugs is approximately 2 hours, but tolcapone is slightly more potent and has a longer duration of action. Tolcapone is taken in a standard dosage of 100 mg three times daily some patients require a daily dose of twice that amount. By contrast, entacapone (200 mg) needs to be taken with each dose of levodopa, up to five times daily. 

See pp. 443-444 for a description of the newly approved drugs, pramipexol, ropinirole and tolcapone. 

Tolcapone [TOLE ka pone] is a nitrocatechol derivative that represents a new class of anti-Parkinson s drugs. It selectively and reversibly inhibits both peripheral and central catechol-O-methyl-transferase (COMT) (Figure 8.11). Normally, the methylation of levo-dopa by COMT to 3-O-methyldopa is a minor pathway for levodopa metabolism. However, when peripheral dopamine decarboxylase activity is inhibited by carbidopa, a significant concentration of 3-O-methyldopa is formed that competes with levodopa for active transport into the CNS. Inhibition of COMT by tolcapone leads to decreased plasma concentrations of 3-O-methyldopa, increased central uptake of levodopa, and greater concentrations of brain dopamine. Tolcapone has been demonstrated to reduce the frequency of the on-off phenomenon. 

Pharmacokinetics Tolcapone, taken orally, is readily absorbed, and its absorption is not influenced by food. It is extensively bound to plasma albumin (>99 percent), and has a small volume of distribution (0.13 L/kg). The plasma half-life is approximately two hours, although inhibition of COMT may last considerably longer due to its affinity for the enzyme. Tolcapone is extensively metabolized, and its metabolites are eliminated in both the urine and feces. Dosage may need to be adjusted in individuals with moderate or severe cirrhosis. 

Catechol O-methyltransferase inhibition represents therefore a valuable adjuvant to the L-DOPA decarboxylase inhibition. Unfortunately, tolcapone exhibited... 

Liljequist R, Haapalinna A, Ahlander M, Li YH, Mannisto PT (1997) Catechol O-methyltransferase inhibitor tolcapone has minor influence on performance in experimental memory models in rats. Behavioural Brain Res 82 195-202... 

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