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

被引:33
作者
Bonifacio, M. J. [1 ]
Sutcliffe, J. S. [2 ]
Torrao, L. [1 ]
Wright, L. C. [1 ]
Soares-da-Silva, P. [1 ,3 ]
机构
[1] BIAL, Dept Res & Dev, P-4745457 Sao Mamede Do Coronado, Portugal
[2] Maccine Pte Ltd, Singapore, Singapore
[3] Univ Porto, Fac Med, Dept Pharmacol & Therapeut, P-4100 Oporto, Portugal
关键词
Opicapone; Levodopa pharmacokinetics; COMT inhibition; Brain microdialysis; Dorsal striatum; Prefrontal cortex; Substantia nigra; Cynomolgus monkeys; CATECHOL-O-METHYLTRANSFERASE; SOMATODENDRITIC DOPAMINE RELEASE; PHASE-III TRIAL; PARKINSONS-DISEASE; DOUBLE-BLIND; TOLCAPONE; MICRODIALYSIS; PATHOGENESIS; PHARMACOLOGY; ENTACAPONE;
D O I
10.1016/j.neuropharm.2013.10.014
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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 mm intervals) for the assays of catecholamine and COMT activity. Results: Opicapone increased levodopa systemic exposure by 2-fold not changing C-max values and reduced both 3-O-methyldopa (3-OMD) exposure and Cmax values by 5-fold. These changes were accompanied by similar to 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. (C) 2013 Elsevier Ltd. All rights reserved.
引用
收藏
页码:334 / 341
页数:8
相关论文
共 35 条
[31]   Molecular pathogenesis of Parkinson's disease: update [J].
Saiki, Shinji ;
Sato, Shigeto ;
Hattori, Nobutaka .
JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY, 2012, 83 (04) :430-436
[32]   Etiology and Pathogenesis of Parkinson's Disease [J].
Schapira, Anthony H. ;
Jenner, Peter .
MOVEMENT DISORDERS, 2011, 26 (06) :1049-1055
[33]   Parkinson's Disease: Genetics and Pathogenesis [J].
Shulman, Joshua M. ;
De Jager, Philip L. ;
Feany, Mel B. .
ANNUAL REVIEW OF PATHOLOGY: MECHANISMS OF DISEASE, VOL 6, 2011, 6 :193-222
[34]   Effects of tolcapone upon soluble and membrane-bound brain and liver catechol-O-methyltransferase [J].
Vieira-Coelho, MA ;
Soares-Da-Silva, P .
BRAIN RESEARCH, 1999, 821 (01) :69-78
[35]   Site-specific role of catechol-O-methyltransferase in dopamine overflow within prefrontal cortex and dorsal striatum [J].
Yavich, Leonid ;
Forsberg, Markus M. ;
Karayiorgou, Maria ;
Gogos, Joseph A. ;
Mannisto, Pekka T. .
JOURNAL OF NEUROSCIENCE, 2007, 27 (38) :10196-10202