Catechol-O-methyltransferase inhibition by U-0521 increases striatal utilization of levodopa.
The effects of U-0521, a catechol-O-methyltransferase (COMT) inhibitor, were studied on this enzyme activity and on Dopa metabolism in rat striatum. In vivo maximal inhibition (95%) of COMT activity was obtained at 5 min with enzyme recovery to 64% of basal activity at 120 min. When injected in increasing doses U-0521 (200 mg . kg-1) inhibited, at 10 min, COMT activity by 85% with an IC50 = 80 mg . kg-1. In rats pretreated with U-0521 and then with DOPA the accumulation of 3-O-methyldopa-(OMD) in the plasma was essentially blocked while Dopa, dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) accumulation in the striatum was significantly higher than in DOPA treated controls. U-0521, a potent COMT inhibitor, enhances the availability and utilization of levodopa in the brain and may thus be helpful in future treatment of parkinsonian patients.
D000818:Animals; D065098:Catechol O-Methyltransferase Inhibitors; D002395:Catecholamines / Q000378:metabolism; D003342:Corpus Striatum / Q000201:enzymology / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D007980:Levodopa / Q000378:metabolism*; D008297:Male; D008750:Methyldopa / Q000378:metabolism; D011427:Propiophenones / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013997:Time Factors
D065098:Catechol O-Methyltransferase Inhibitors; D002395:Catecholamines; D011427:Propiophenones; D007980:Levodopa; C006104:U 0521; D008750:Methyldopa