OBJECTIVES: Entacapone is a highly potent, reversible, peripherally acting 
catechol-O-methyl transferase (COMT) inhibitor that is used as an adjunct to 
L-dopa in the treatment of patients with Parkinson disease (PD). Nevertheless, 
the consequence of the long-lasting inhibition of COMT by entacapone has never 
been investigated. We assessed the variation of the soluble red blood cell 
(S-RBC)-COMT activity after 3 months of chronic treatment by entacapone.
METHODS: Twelve consecutive white PD patients (3 women and 9 men; mean age, 65.7 
± 2.4 years) with L-dopa-related motor fluctuations were assessed. Entacapone 
200 mg was given in combination with each scheduled L-dopa/dopa decarboxylase 
inhibitor dose (range, 3-5 doses daily). The S-RBC-COMT activity was determined 
both before entacapone administration (baseline) and twice, respectively, after 
1 and 3 months treatment with entacapone, that is, on morning, after at least a 
12-hour withdrawal of entacapone and L-dopa and before the following first daily 
administration.
RESULTS: Mean baseline S-RBC-COMT activity was 0.72 ± 0.09 pmol/min per 
milligram (range, 0.30-1.29 pmol/min per milligram) of protein. After 3 months, 
the level increased significantly in all PD patients from 0.72 ± 0.09 pmol/min 
per milligram (range, 0.30-1.29 pmol/min per milligram) to 1.19 ± 0.13 pmol/min 
per milligram (range, 0.58-2.14 pmol/min per milligram) of protein (P < 0.01), 
which corresponds to a mean increase of 72.9 ± 9.2% (range, 24%-146%).
CONCLUSIONS: Our findings suggest that a long-lasting inhibition of the COMT may 
limit the efficacy of entacapone by development of a tolerance. Moreover, one 
may assume that an abrupt withdrawal of the treatment will be followed by a 
dramatic worsening of motor disability.