title: COMT-inhibition increases serum levels of dihydroxyphenylacetic acid (DOPAC) in patients with advanced Parkinson's disease.
abstract: Inhibition of the catechol-O-methyltransferase (COMT) is an effective treatment for end-of-dose fluctuations in advanced Parkinson's disease. The aim of the present investigation was to analyse the consequences of subsequent alterations in levodopa metabolism under common treatment conditions when the levodopa dose is adjusted due to the occurrence of dyskinesias after initiation of the COMT-inhibitor. Ten patients with advanced Parkinson's disease (Hoehn & Yahr stage IV) were medicated with tolcapone. Prior to and five to ten days after the initiation of tolcapone 300 mg/d, serum level profiles of levodopa and its metabolites (3-O-methyldopa (3-OMD), dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA)) were performed. The mean daily levodopa dose was reduced from 894 +/- 248 mg to 646 +/- 252 mg (p = 0.003). There was a significant increase in the area under the curve (AUC) of DOPAC during COMT-inhibition compared to the baseline profile (p = 0.009). There were significant decreases of the AUC of HAV (p = 0.001) and the ratios of the AUC HVA / AUC DOPAC (p = 0.0001) and AUC 3-OMD / AUC levodopa (p = 0.0001).
  
  
  CONCLUSIONS
  The elevation of DOPAC and the decrease of HVA and HVA / DOPAC reflect a shift of the levodopa metabolism towards the MAO-B dependent oxidative pathway. This might contribute to production of hydroxyl radicals and induction of oxidative stress.
authors.affiliation: Neurological Clinic, Justus-Liebig-Universität, Giessen, Germany. Matthias.Oeschner@neuro.med.uni-giessen.de
authors.forename: M
authors.initials: M
authors.lastname: Oechsner
authors.forename: C
authors.initials: C
authors.lastname: Buhmann
authors.forename: J
authors.initials: J
authors.lastname: Strauss
authors.forename: H J
authors.initials: HJ
authors.lastname: Stuerenburg
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000097:blood*; D000368:Aged; D000369:Aged, 80 and over; D000978:Antiparkinson Agents / Q000627:therapeutic use*; D001577:Benzophenones / Q000627:therapeutic use*; D065098:Catechol O-Methyltransferase Inhibitors; D004295:Dihydroxyphenylalanine / Q000031:analogs & derivatives* / Q000097:blood; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D005260:Female; D006719:Homovanillic Acid / Q000097:blood; D006801:Humans; D007980:Levodopa / Q000008:administration & dosage / Q000097:blood / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009596:Nitrophenols; D010300:Parkinson Disease / Q000097:blood* / Q000188:drug therapy* / Q000503:physiopathology; D000077867:Tolcapone; D014443:Tyrosine / Q000031:analogs & derivatives
chemical_list: D000978:Antiparkinson Agents; D001577:Benzophenones; D065098:Catechol O-Methyltransferase Inhibitors; D009596:Nitrophenols; D015102:3,4-Dihydroxyphenylacetic Acid; D014443:Tyrosine; D007980:Levodopa; D004295:Dihydroxyphenylalanine; D000077867:Tolcapone; C008404:3-methoxytyrosine; D006719:Homovanillic Acid