Pharmacological profile of opicapone, a third‐generation nitrocatechol catechol‐O‐methyl transferase inhibitor, in the rat

Abstract

The pharmacodynamic effects of opicapone were explored by evaluating rat COMT activity and levodopa pharmacokinetics, in the periphery through microdialysis and in whole brain. The potential cytotoxicity risk of opicapone was explored in human hepatocytes by assessing cellular ATP content and mitochondrial membrane potential. KEY RESULTSOpicapone inhibited rat peripheral COMT with ED50 values below 1.4 mg·kg −1 up to 6 h post-administration. The effect was sustained over the first 8 h and by 24 h COMT had not returned to control values. A single administration of opicapone resulted in increased and sustained plasma levodopa levels with a concomitant reduction in 3-O-methyldopa from 2 h up to 24 h post-administration, while tolcapone produced significant effects only at 2 h post-administration. The effects of opicapone on brain catecholamines after levodopa administration were sustained up to 24 h post-administration. Opicapone was also the least potent compound in decreasing both the mitochondrial membrane potential and the ATP content in human primary hepatocytes after a 24 h incubation period. CONCLUSIONS AND IMPLICATIONSOpicapone has a prolonged inhibitory effect on peripheral COMT, which extends the bioavailability of levodopa, without inducing toxicity. Thus, it exhibits some improved properties compared to the currently available COMT inhibitors. Abbreviations

Spotlight on opicapone as an adjunct to levodopa in Parkinson’s disease: design, development and potential place in therapy

“…In one study, OPC was given orally to rats and resulted in significant reduction in COMT activity 31. The maximum plasma concentration was detected at 4 h following administration.…”

“…OPC could not be detected after 8 h post-admission. When LD/BZ was given to rats 2 h and 24 h after administration of OPC, the maximum plasma concentration of LD increased by 1.6- and 1.4-fold, bioavailability of LD increased by 1.9-and 1.3-fold and 3-OMD exposure decreased by 6.3- and 1.6-fold, respectively 31. In the same study, adenosine triphosphate (ATP) concentrations and mitochondrial membrane potentials were measured after 24 h of incubation of human primary hepatocytes to investigate cytotoxic properties.…”

Development of a liquid chromatography assay for the determination of opicapone and BIA 9–1079 in rat matrices

“…In fact, nonclinical studies performed in Wistar rats revealed that opicapone has a higher activity as a peripheral COMT inhibitor than tolcapone, with median effective doses (ED 50 ) at 3h post-dose of 1.05 ± 0.04 and 1.77 ± 0.10 mg/kg, respectively (Kiss et al, 2010). In another study, opicapone also inhibited the rat peripheral COMT more efficiently than tolcapone (Bonifácio et al, 2015); however, as expected, contrary to tolcapone, opicapone does not inhibit the central COMT (Kiss et al, 2010;Bonifácio et al, 2015). Anyway, opicapone is a longer-acting inhibitor than tolcapone and entacapone, with 50% of peripheral COMT inhibition maintained up to 24 h after a single administration to rats (Kiss et al, 2010).…”

“…Anyway, opicapone is a longer-acting inhibitor than tolcapone and entacapone, with 50% of peripheral COMT inhibition maintained up to 24 h after a single administration to rats (Kiss et al, 2010). Furthermore, when administered with levodopa/benserazide (an AADC inhibitor), opicapone was demonstrated to increase two-fold the initial levodopa plasma levels in rats and kept these levels stable for at least 24 h (Kiss et al, 2010;Bonifácio et al, 2015). Recent clinical studies also revealed that opicapone increases more significantly the levodopa bioavailability in comparison to entacapone (Rocha et al, 2014).…”

Effect of opicapone multiple‐dose regimens on levodopa pharmacokinetics

“…One h after administration, COMT inhibition was 99% with OPC vs. 82% with tolcapone and 68% with entacapone. Nine hours after administration, entacapone showed no COMT inhibition and tolcapone produced minimal inhibitory effect (16%), whereas OPC continued to inhibit COMT activity by 91% .…”