Reduction of circulating 3-O-methyldopa by inhibition of catechol-O-methyltransferase with OR-611 and OR-462 in cynomolgus monkeys: implications for the treatment of Parkinson's disease.
We studied the effectiveness of OR-611 and OR-462, two novel inhibitors of the enzyme catechol-O-methyltransferase (COMT), on 3-O-methyldopa (OMD) formation in cynomolgus monkeys following intravenous levodopa administration. OR-611 dose-dependently reduced the area under the OMD concentration-vs-time curve, reduced maximum plasma OMD concentrations, delayed the time to peak OMD levels, reduced systemic levodopa clearance, and prolonged the elimination half-life of levodopa. Similar effects on peripheral levodopa metabolism were seen with doses of 15 mg/kg of OR-611 and OR-462, its sister compound, which lacks the ability to penetrate the central nervous system (CNS).
Cedarbaum
J M
JM
Department of Neurology and Neuroscience, Cornell University Medical College, Burke Rehabilitation Center, White Plains, New York.
Leger
G
G
Guttman
M
M
D000818:Animals; D065098:Catechol O-Methyltransferase Inhibitors; D002396:Catechols / Q000493:pharmacokinetics / Q000494:pharmacology*; D007980:Levodopa / Q000097:blood / Q000378:metabolism; D008252:Macaca fascicularis; D008297:Male; D009570:Nitriles; D010300:Parkinson Disease / Q000188:drug therapy / Q000378:metabolism*; D010422:Pentanones / Q000493:pharmacokinetics / Q000494:pharmacology*; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000097:blood / Q000378:metabolism
D065098:Catechol O-Methyltransferase Inhibitors; D002396:Catechols; D009570:Nitriles; D010422:Pentanones; D014443:Tyrosine; D007980:Levodopa; C071192:entacapone; C057364:nitecapone; C008404:3-methoxytyrosine