Inhibition of catechol‐O‐methyltransferase contributes to more stable levodopa plasma levels

Abstract

The short plasma half-life limits the antiparkinsonian efficacy of levodopa/carbidopa (LD/CD). Administration of LD/CD with the catechol-O-methyltransferase inhibitor entacapone in one tablet (LCE) may extend plasma half-life of LD and thus its effect on motor symptoms in patients with Parkinson's disease (PD). The objectives of this study were to monitor the motor response to a switch from LD/CD to LCE by a simultaneous performance of an instrumental motor test and rating of motor symptoms and to compare the LD plasma behavior between both conditions in terms of stability. Twenty-one treated PD patients received LD/CD and then the identical oral LD dosage of LCE within a standardized setting on 2 consecutive days. Rating better reflected the motor improvement after LD application than the instrumental test. Motor symptoms of PD patients decreased significantly more during the LCE than the LD/CD condition, probably due to significantly higher LD plasma levels and a significantly less pronounced fall of the LD concentrations following the second LD intake. Our study shows a more stable LD plasma behavior during LCE intake and accordingly a better effect on motor symptoms according to rating outcomes and motor test results to a lesser extent.

The scientific and clinical basis for the treatment of Parkinson disease (2009)

“…COMT inhibitors are effective when administered in conjunction with either regular or sustained-release Sinemet 395 and increase interdose, trough, and mean levodopa concentrations. 396 Thus, administration of levodopa plus a COMT inhibitor results in smoother plasma levodopa levels and more continuous brain availability compared with levodopa alone. 396 This can be illustrated with FD-PET studies, which demonstrate increased and more sustained striatal FD uptake when levodopa/carbidopa is administered with a COMT inhibitor.…”

“…396 Thus, administration of levodopa plus a COMT inhibitor results in smoother plasma levodopa levels and more continuous brain availability compared with levodopa alone. 396 This can be illustrated with FD-PET studies, which demonstrate increased and more sustained striatal FD uptake when levodopa/carbidopa is administered with a COMT inhibitor. 397 Thus, administering levodopa with a COMT inhibitor has the potential to deliver levodopa to the brain in a more predictable and stable fashion, thus decreasing the fluctuations in levodopa concentrations seen when standard levodopa is administered intermittently.…”

Neurotoxicity and Metabolism of the Catecholamine-Derived 3,4-Dihydroxyphenylacetaldehyde and 3,4-Dihydroxyphenylglycolaldehyde: The Role of Aldehyde Dehydrogenase

“…Genetic variations in COMT have been associated with a variety of diverse clinical phenotypes, most notably with psychiatric conditions including schizophrenia (Craddock et al, 2006). L-dopa is a substrate for COMT, and high COMT activity has been associated with poor therapeu-144 tic management of PD and an increased incidence of drug-induced toxicity (Muller et al, 2006).…”

Levodopa/carbidopa and entacapone in the treatment of Parkinson’s disease: efficacy, safety and patient preference

“…Both kinds of motor complications are combined with appearance of a wide array of non-motor symptoms 1,11–13. Various central-related hypotheses exist on the origin of these LD-associated motor complications.…”