Tolcapone

Molecular formula C14H11NO5 Molecular weigM 273.24 CAS Registry No 134308-13-7 Merck Index 13, 9585 

Sample preparation Mix 200 xL plasma with 25 ixL IS in MeCN, add 300 ixL MeCN, let stand at 4° for 15 min, centrifuge for 5 min. Rfc 100 aL of the supernatant with 100 p.L 50 mM pH 2 sodium dihydrogen phosphate buffer, inject an 80 lL aUquot. 

Mobile phase MeOH THF buffer 55 45 5 (Prepare the buffer by mixing 550 ml. MeOH containing 11.5 g/L Af-hexylmethylamine with 450 mL 50 mM sodium dihydrogen phosphate, adjust apparent pH to 2.1 with phosphoric acid, add 50 mL THF.) 

Internal standard 3-hydroxy-4-methoxy-4 -methyl-5-nitrohenzophenone (10.5) 

Heizmsinn, P. Schmitt, M. Leube, J. Martin, H. Saner, A. Determination of the catechol-O-methyl-transferase inhibitor tolcapone and three of its metabolites in animal and humsm plasma smd urine by reversed-phase high-performance liquid chromatography with ultraviolet detection, J.Chromatogr.B, 1999, 730, 153-160. 

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Second generation COMT inhibitors were developed by three laboratories in the late 1980s. Apart from CGP 28014, nitrocatechol is the key structure of the majority of these molecules (Fig. 3). The current COMT inhibitors can be classified as follows (i) mainly peripherally acting nitrocatechol-type compounds (entacapone, nitecapone, BIA 3-202), (ii) broad-spectrum nitrocatechols having activity both in peripheral tissues and the brain (tolcapone, Ro 41-0960, dinitrocatechol, vinylphenylk-etone), and (iii) atypical compounds, pyridine derivatives (CGP 28014,3-hydroxy-4-pyridone and its derivatives), some of which are not COMT inhibitors in vitro but inhibit catechol O-methylation by some other mechanism. The common features of the most new compounds are excellent potency, low toxicity and activity through oral administration. Their biochemical properties have been fairly well characterized. Most of these compounds have an excellent selectivity in that they do not affect any other enzymes studied [2,3]. 

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... 

Catechol-O-Methyltransferase. Figure 4 Rat model of Parkinson s disease. Comparison of entacapone, tolcapone and CGP 28014 in the rat turning model of Parkinson s disease [4]. 

In patients having Parkinson s disease, both entacapone and tolcapone potentiate the therapeutic effect of L-dopa and prolong the daily ON time by 1-2 h. In the clinic, COMT inhibitors have been well tolerated, and the number of premature terminations has been low. In general, the incidence of adverse events has been higher in tolcapone-treated patients than in entacapone-treated patients. The main events have comprised of dopaminergic and gastrointestinal problems [2,3]. 

The dopamine precursor l-DOPA (levodopa) is commonly used in TH treatment of the symptoms of PD. l-DOPA can be absorbed in the intestinal tract and transported across the blood-brain barrier by the large neutral amino acid (LNAA) transport system, where it taken up by dopaminergic neurons and converted into dopamine by the activity of TH. In PD treatment, peripheral AADC can be blocked by carbidopa or benserazide to increase the amount of l-DOPA reaching the brain. Selective MAO B inhibitors like deprenyl (selegiline) have also been effectively used with l-DOPA therapy to reduce the metabolism of dopamine. Recently, potent and selective nitrocatechol-type COMT inhibitors such as entacapone and tolcapone have been shown to be clinically effective in improving the bioavailability of l-DOPA and potentiating its effectiveness in the treatment of PD. 

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. 

Tolcapone Keep all appointments with the primary care provider. Laver function tests are performed... 

Discuss the special considerations the nurse should be aware of when administering tolcapone. 

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). 

ENTACAPONE CARBI[X>PA SELEGILINE TOLCAPONE BENSERAZIDE [Pg.306]

The deamination of DA to DOPAC can be prevented by MAOb inhibitors such as selegiline while COMT inhibitors stop its further o-methylation to HVA and the conversion of dopa to OMD. COMT inhibitors can act just peripherally (entacapone) or in the CNS as well (tolcapone). DD — dopa decarboxylase MAO—monoamine oxidase COMT—catechol-o-methyl transferase... 

Tolcapone (Tasmar ) Peripherally blocks COMT metabolism of DA some central activity Start with 1 00 mg with first Sinemet dose once daily if symptoms continue, increase to 2 and then 3 times daily, then to 200 mg each dose usual MD is 1 00 three times daily to minimize risk of side-effects... 

Tolcapone has been associated with several cases of severe liver failure, including fatalities, and has been removed from the market in some countries. Thus, it should only be used in patients who cannot take or do not respond to entacapone. Serum alanine aminotransferase and aspartate aminotransferase concentrations should be monitored at baseline, then every 2 to 4 weeks for 6 months, and then periodically for the remainder of therapy. Patients who fail to show symptomatic benefit after 3 weeks should discontinue tolcapone. Entacapone has not been associated with liver damage, so monitoring of liver enzymes is not currently recommended.24,25,29... 

Tolcapone (Tasmar) and entacapone (Comtan) are used only in conjunction with carbidopa/L-dopa to prevent the peripheral conversion of L-dopa to dopamine (increasing the area under the curve of L-dopa by approximately 35%). Thus, on time is increased by about 1 hour. These agents significantly decrease off time and decrease L-dopa requirements. Concomitant use of nonselective MAO inhibitors should be avoided to prevent inhibition of the pathways for normal catecholamine metabolism. 

The starting and recommended dose of tolcapone is 100 mg three times daily as an adjunct to carbidopa/L-dopa. Its use is limited by the potential for fatal liver toxicity. Strict monitoring of liver function is required, and tolcapone should be discontinued if liver function tests are above the upper limit of normal or any signs or symptoms suggestive of hepatic failure exist. It should be reserved for patients with fluctuations that have not responded to other therapies. 

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. 

FIGURE 5.8 Structures of tolcapone and entacapone —only the nitro group of tolcapone is extensively reduced in vivo. 

Smith KS, Smith PL, Heady TN, et al. In vitro metabolism of tolcapone to reactive intermediates relevance to tolcapone liver toxicity. Chem Res Toxicol 2003 16(2) 123—128. 

Tolcapone (Tasmar) Parkinson s disease Hepatic toxicity 1998 [59]... 

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. 

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