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When levodopa therapy is used in Parkinson's disease, degradation of the drug in the peripheral nervous system is associated with dyskinesias and motor fluctuations. Much of this degradation is produced by catechol-O-methyltransferase (COMT), an enzyme involved in the metabolism of catecholamines and catechol compounds. Inhibition of COMT activity prolongs the action of levodopa and reduces fluctuations in response. Entacapone is a selective inhibitor of COMT whose activity is primarily in the peripheral nervous system, with little effect in the central nervous system. This paper reviews the pharmacologic properties and clinical usefulness of entacapone in the treatment of Parkinson's disease. Recent studies, abstracts, and reviews published in the English-language literature were identified through searches of MEDLINE (1966-September 2000), International Pharmaceutical Abstracts (1970-September 2000), and PharmaProjects (September 2000 version), and from the Web sites of Parkinson's disease conferences held from 1996 to September 2000. Relevant human studies provided further information on the pharmacologic properties and clinical usefulness of entacapone. Entacapone is rapidly absorbed, with a time to maximum concentration of approximately 1 hour. Its plasma elimination half-life is 0.4 to 0.7 hour in the beta phase and 2.4 hours in the gamma phase, and it has 35% absolute bioavailability after oral administration, secondary to first-pass clearance. Entacapone is 98% protein bound; thus, it is not distributed widely in tissues and is almost completely metabolized before excretion (0.1%-0.2% of dose unchanged in urine). The drug inhibits erythrocyte-soluble COMT activity in a dose-dependent fashion (48% after a 400-mg dose, 82% after an 800-mg dose). The inhibitory effect is reversible, with recovery of soluble COMT activity within 4 to 8 hours. In levodopa-treated patients with Parkinson's disease who experience motor fluctuations, clinical trials have demonstrated entacapone's effectiveness in increasing "on" time (the period during which medications relieve the symptoms of Parkinson's disease) by up to 1.2 hours, decreasing "off" time (the period during which symptoms increase) by 0.9 to 1.3 hours, and producing overall total improvement in scores on the Unified Parkinson's Disease Rating Scale. The recommended dosage of entacapone is 200 mg administered orally with each dose of levodopa/carbidopa, up to 8 doses per day. The drug is generally well tolerated, with most adverse effects attributed to levodopa-related dopaminergic effects, including dyskinesias and nausea. In clinical trials, adjuvant treatment with entacapone appeared to be an effective and well-tolerated therapeutic strategy in patients with Parkinson's disease who experience fluctuations in the response to levodopa therapy. The increased elimination half-life of levodopa with concomitant entacapone results in greater and more sustained plasma levodopa levels, with more constant dopaminergic stimulation in the brain and greater amelioration of parkinsonian symptoms.


J Najib. Entacapone: a catechol-O-methyltransferase inhibitor for the adjunctive treatment of Parkinson's disease. Clinical therapeutics. 2001 Jun;23(6):802-32; discussion 771

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PMID: 11440283

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