title: Brain and peripheral pharmacokinetics of levodopa in the cynomolgus monkey following administration of opicapone, a third generation nitrocatechol COMT inhibitor.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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 mg/kg opicapone for 14 days. Twenty-three hours after last administration of vehicle or opicapone, animals were challenged with levodopa/benserazide (12/3 mg/kg). Extracellular dialysate and blood samples were collected over 360 min (at 30 min intervals) for the assays of catecholamine and COMT activity.
  
  
  RESULTS
  Opicapone increased levodopa systemic exposure by 2-fold not changing Cmax values and reduced both 3-O-methyldopa (3-OMD) exposure and Cmax values by 5-fold. These changes were accompanied by ∼76-84% 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Research & Development, BIAL, 4745-457 São Mamede do Coronado, Portugal.
authors.forename: M J
authors.initials: MJ
authors.lastname: Bonifácio
authors.affiliation: Maccine Pte Ltd., 10 Science Park Road, #01-05 The Alpha, Singapore Science Park II, Singapore.
authors.forename: J S
authors.initials: JS
authors.lastname: Sutcliffe
authors.affiliation: Department of Research & Development, BIAL, 4745-457 São Mamede do Coronado, Portugal.
authors.forename: L
authors.initials: L
authors.lastname: Torrão
authors.affiliation: Department of Research & Development, BIAL, 4745-457 São Mamede do Coronado, Portugal.
authors.forename: L C
authors.initials: LC
authors.lastname: Wright
authors.affiliation: Department of Research & Development, BIAL, 4745-457 São Mamede do Coronado, Portugal; Department of Pharmacology & Therapeutics, Faculty of Medicine, University Porto, Porto, Portugal. Electronic address: psoares.silva@bial.com.
authors.forename: P
authors.initials: P
authors.lastname: Soares-da-Silva
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D065098:Catechol O-Methyltransferase Inhibitors; D018592:Cross-Over Studies; D015259:Dopamine Agents / Q000493:pharmacokinetics*; D004347:Drug Interactions; D005260:Female; D007980:Levodopa / Q000493:pharmacokinetics*; D008252:Macaca fascicularis; D008297:Male; D010069:Oxadiazoles / Q000494:pharmacology*; D010300:Parkinson Disease / Q000188:drug therapy
chemical_list: D000978:Antiparkinson Agents; D065098:Catechol O-Methyltransferase Inhibitors; D015259:Dopamine Agents; D010069:Oxadiazoles; D007980:Levodopa; C549349:opicapone
keywords: 3-Methoxy-4-hydroxyphenylglycol; 3-O-methyldopa; 3-OMD; AADC; AUC; Brain microdialysis; C(max); COMT; COMT inhibition; Cynomolgus monkeys; DOPAC; Dorsal striatum; EDTA; HPLC-ED; HVA; Hb; Levodopa pharmacokinetics; MN; MOPEG; Opicapone; PCA; PD; Parkinson's disease; Prefrontal cortex; Substantia nigra; aCSF; area under the curve; aromatic amino acid decarboxylase; artificial cerebrospinal fluid; catechol-O-methyltransferase; dihydroxyphenylacetic acid; ethylenediaminetetraacetic acid; haemoglobin; high pressure liquid chromatography with electrochemical detection; homovanillic acid; maximum concentration; metanephrine; perchloric acid; t(max); time to C(max)