title: The COMT Val158Met polymorphism affects the response to entacapone in Parkinson's disease: a randomized crossover clinical trial.
abstract: OBJECTIVE
  In Parkinson disease (PD), the selective C-O-methyltransferase (COMT) inhibitor entacapone prolongs the effect of levodopa on motor symptoms (ON time) by increasing its bioavailability. The COMT Val158Met polymorphism is equally distributed in PD patients and modulates COMT activity, which can be high (Val/Val, COMT(HH) ), intermediate (Val/Met, COMT(HL) ), or low (Met/Met, COMT(LL) ). The objective of this study was to determine the response to entacapone in COMT(HH) and COMT(LL) PD patients.
  
  
  METHODS
  Thirty-three PD patients, homozygous for the COMT alleles COMT(HH) (n = 17) and COMT(LL) (n = 16), were randomized in a double-blind crossover trial consisting of 2 successive acute levodopa challenges associated with 200mg entacapone or placebo. The primary endpoint was the gain in the best ON time. Secondary endpoints were levodopa pharmacokinetics and COMT activity in red blood cells.
  
  
  RESULTS
  The gain in the best ON time was higher in COMT(HH) than in COMT(LL) patients (39 ± 10 vs 9 ± 9 minutes, p = 0.04, interaction between treatment and genotype). Area under the concentration over time curve of levodopa increased more after entacapone in COMT(HH) than in COMT(LL) patients (+62 ± 6% vs +34 ± 8%, p = 0.01). COMT inhibition by entacapone was higher in COMT(HH) than in COMT(LL) patients (-0.54 ± 0.07 vs -0.31 ± 0.06 pmol/min/mg protein, p = 0.02).
  
  
  CONCLUSIONS
  The COMT(HH) genotype in PD patients enhances the effect of entacapone on the pharmacodynamics and pharmacokinetics of levodopa. The response to entacapone after repeated administrations and in heterozygous patients remains to be determined.
authors.affiliation: INSERM (French National Institute of Medical Research and Health), Clinical Investigation Center (CIC-9503), Pitié-Salpêtrière Hospital, Paris, France. jean-christophe.corvol@psl.aphp.fr
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Corvol
authors.forename: Cécilia
authors.initials: C
authors.lastname: Bonnet
authors.forename: Fanny
authors.initials: F
authors.lastname: Charbonnier-Beaupel
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Bonnet
authors.forename: Marie-Hélène
authors.initials: MH
authors.lastname: Fiévet
authors.forename: Agnès
authors.initials: A
authors.lastname: Bellanger
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Roze
authors.forename: Gayané
authors.initials: G
authors.lastname: Meliksetyan
authors.forename: Mouna
authors.initials: M
authors.lastname: Ben Djebara
authors.forename: Andreas
authors.initials: A
authors.lastname: Hartmann
authors.forename: Lucette
authors.initials: L
authors.lastname: Lacomblez
authors.forename: Cédric
authors.initials: C
authors.lastname: Vrignaud
authors.forename: Noël
authors.initials: N
authors.lastname: Zahr
authors.forename: Yves
authors.initials: Y
authors.lastname: Agid
authors.forename: Jean
authors.initials: J
authors.lastname: Costentin
authors.forename: Jean-Sébastien
authors.initials: JS
authors.lastname: Hulot
authors.forename: Marie
authors.initials: M
authors.lastname: Vidailhet
mesh_terms: D000368:Aged; D000978:Antiparkinson Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001682:Biological Availability; D002394:Catechol O-Methyltransferase / Q000235:genetics*; D065098:Catechol O-Methyltransferase Inhibitors; D002396:Catechols / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005260:Female; D005838:Genotype; D006801:Humans; D007980:Levodopa / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use; D008297:Male; D008715:Methionine / Q000235:genetics; D008875:Middle Aged; D009570:Nitriles / Q000493:pharmacokinetics / Q000627:therapeutic use*; D010300:Parkinson Disease / Q000188:drug therapy* / Q000235:genetics; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D014633:Valine / Q000235:genetics
chemical_list: D000978:Antiparkinson Agents; D065098:Catechol O-Methyltransferase Inhibitors; D002396:Catechols; D004791:Enzyme Inhibitors; D009570:Nitriles; D007980:Levodopa; C071192:entacapone; D008715:Methionine; D002394:Catechol O-Methyltransferase; D014633:Valine