title: Graphical analysis of 6-fluoro-L-dopa trapping: effect of inhibition of catechol-O-methyltransferase.
abstract: Graphical methods to analyze tracer time-course data allow reliable quantitation of the rate of incorporation of tracer from plasma into a "trapped" kinetic component, even when the details of the kinetic model are unknown. Applications of the method over long time periods often expose the slow reversibility of the trapping process. In the extended graphical method, both trapping rate and a presumed first-order loss rate constant are estimated simultaneously from the time-course data.
  
  
  METHODS
  We applied the extended graphical method to 6-fluoro-L-dopa (6-FD), simultaneously estimating the rate of uptake (Ki) and the rate constant for loss from the trapped component (K(loss)) in a single fitting procedure. We applied this approach to study the effects of two catechol-O-methyl-transferase inhibitors on the kinetics of 6-FD in cynomolgus monkeys.
  
  
  RESULTS
  Inhibition of peripheral O-methylation with either inhibitor, confirmed by high-performance liquid chromatography analysis of labeled compounds in arterial plasma, had no significant effect on Ki, in agreement with previously reported studies. In contrast, tolcapone, a catechol-O-methyl-transferase inhibitor, having central effects in addition to peripheral effects at the dosage used, decreased K(loss) by 40% from control values (p < 0.002), whereas nitecapone, which has no known central activity, had no significant effect.
  
  
  CONCLUSIONS
  This method provides insight into the neurochemical basis for the kinetic behavior of 6-FD in both health and disease and may be used to define the action of centrally active drugs that influence the metabolism of dopamine.
authors.affiliation: Department of Medical Physics, University of Wisconsin, Madison, USA.
authors.forename: J E
authors.initials: JE
authors.lastname: Holden
authors.forename: D
authors.initials: D
authors.lastname: Doudet
authors.forename: C J
authors.initials: CJ
authors.lastname: Endres
authors.forename: G L
authors.initials: GL
authors.lastname: Chan
authors.forename: K S
authors.initials: KS
authors.lastname: Morrison
authors.forename: F J
authors.initials: FJ
authors.lastname: Vingerhoets
authors.forename: B J
authors.initials: BJ
authors.lastname: Snow
authors.forename: B D
authors.initials: BD
authors.lastname: Pate
authors.forename: V
authors.initials: V
authors.lastname: Sossi
authors.forename: K R
authors.initials: KR
authors.lastname: Buckley
authors.forename: T J
authors.initials: TJ
authors.lastname: Ruth
mesh_terms: D000818:Animals; D001577:Benzophenones / Q000494:pharmacology; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D002394:Catechol O-Methyltransferase / Q000502:physiology; D065098:Catechol O-Methyltransferase Inhibitors; D002396:Catechols / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D004295:Dihydroxyphenylalanine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005462:Fluorine Radioisotopes; D008252:Macaca fascicularis; D008297:Male; D009596:Nitrophenols; D010422:Pentanones / Q000494:pharmacology; D000077867:Tolcapone; D014055:Tomography, Emission-Computed
chemical_list: D001577:Benzophenones; D065098:Catechol O-Methyltransferase Inhibitors; D002396:Catechols; D004791:Enzyme Inhibitors; D005462:Fluorine Radioisotopes; D009596:Nitrophenols; D010422:Pentanones; C043437:fluorodopa F 18; D004295:Dihydroxyphenylalanine; C057364:nitecapone; D000077867:Tolcapone; D002394:Catechol O-Methyltransferase