Brain and peripheral pharmacokinetics of levodopa in the cynomolgus monkey following administration of opicapone, a third generation nitrocatechol COMT inhibitor

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• 作者：M.J. Bonif谩cio ; J.S. Sutcliffe ; L. Torr茫o ; L.C. Wright ; P. Soares-da-Silva
• 关键词：Opicapone ; Levodopa pharmacokinetics ; COMT inhibition ; Brain microdialysis ; Dorsal striatum ; Prefrontal cortex ; Substantia nigra ; Cynomolgus monkeys
• 刊名：Neuropharmacology
• 出版年：February, 2014
• 年：2014
• 卷：77
• 期：Complete
• 页码：334-341
• 全文大小：767 K

文摘

4 class="h4">Objective4>The present study aimed at evaluating the effect of opicapone, a third generation nitrocatechol catechol-O-methyltransferase (COMT) inhibitor, on the systemic and central bioavailability of 3,4-dihydroxy-l-phenylalanine (levodopa) and related metabolites in the cynomolgus monkey.4 class="h4">Methods4>

Four monkeys, implanted with guiding cannulas for microdialysis probes, in the substantia nigra, dorsal striatum and prefrontal cortex, were randomized in two groups that received, in a crossover design, vehicle or 100聽mg/kg opicapone for 14 days. Twenty-three hours after last administration of vehicle or opicapone, animals were challenged with levodopa/benserazide (12/3聽mg/kg). Extracellular dialysate and blood samples were collected over 360聽min (at 30聽min intervals) for the assays of catecholamine and COMT activity.4 class="h4">Results4>

Opicapone increased levodopa systemic exposure by 2-fold not changing C_max values and reduced both 3-O-methyldopa (3-OMD) exposure and C_max values by 5-fold. These changes were accompanied by 鈭?6-84% reduction in erythrocyte COMT activity. In dorsal striatum and substantia nigra, opicapone increased levodopa exposure by 1.7- and 1.4-fold, respectively, reducing 3-OMD exposure by 5- and 7-fold respectively. DOPAC exposure was increased by 4-fold in the substantia nigra. In the prefrontal cortex, opicapone increased levodopa exposure and reduced 3-OMD levels by 2.3- and 2.4-fold, respectively.4 class="h4">Conclusions4>

Opicapone behaved as long-acting COMT inhibitor that markedly increased systemic and central levodopa bioavailability. Opicapone is a strong candidate to fill the unmet need for COMT inhibitors that lead to more sustained levodopa levels in Parkinson's disease patients.