title: The effect of carbidopa and entacapone pretreatment on the L-dopa pharmacokinetics and metabolism in blood plasma and skeletal muscle in beagle dog: an in vivo microdialysis study.
abstract: The effects of carbidopa and entacapone pretreatment on the pharmacokinetics and metabolism of i.v. administered L-3,4-dihydroxyphenylalanine (L-dopa) have been examined in vivo in blood plasma and skeletal muscle extracellular fluid (ECF), in beagle dog, by microdialysis. Both with or without carbidopa, blood plasma L-dopa levels declined biexponentially after the i.v. administration of L-dopa. In contrast to blood plasma, a monoexponential decline was observed in muscle ECF in both these pharmacological conditions. Pretreatment with carbidopa had no significant effect on the pharmacokinetic parameters of L-dopa in blood plasma, but resulted in an increase in the area under the concentration versus time curve (AUC) and elimination half-life (t1/2) of L-dopa in muscle ECF (0.61 hr), compared with values achieved after L-dopa alone. Carbidopa pretreatment enhanced the accumulation of 3-O-methyldopa (3-OMD) and dopamine (DA) in muscle ECF but decreased that of L-3,4-dihydroxyphenylacetic acid (DOPAC) in both blood plasma and muscle ECF. Entacapone had a pronounced inhibitory effect on the formation of 3-OMD, resulting in a reduction of the AUC for 3-OMD by 98% and 85% in blood plasma and muscle ECF, respectively. Pretreatment with carbidopa plus entacapone enhanced the Tmax of L-dopa in muscle ECF compared with the values achieved after pretreatment with carbidopa alone. In addition, the elimination half-life (2.66 hr) and volume of distribution by area of L-dopa in blood plasma and its AUC and t1/2 in muscle ECF (1.80 hr) were enhanced substantially. No DA was detected, but DOPAC levels were enhanced in both blood plasma and muscle ECF. These results suggested that carbidopa has a L-dopa-sparing effect in skeletal muscle, which is further enhanced by entacapone.
authors.affiliation: Department of Neurology, University Hospital AZ-VUB, Vrije Universiteit Brussel, Belgium.
authors.forename: D
authors.initials: D
authors.lastname: Deleu
authors.forename: S
authors.initials: S
authors.lastname: Sarre
authors.forename: G
authors.initials: G
authors.lastname: Ebinger
authors.forename: Y
authors.initials: Y
authors.lastname: Michotte
mesh_terms: D000818:Animals; D002230:Carbidopa / Q000008:administration & dosage / Q000494:pharmacology*; D002396:Catechols / Q000008:administration & dosage / Q000494:pharmacology*; D004285:Dogs; D005110:Extracellular Space / Q000378:metabolism; D007980:Levodopa / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D017551:Microdialysis; D018482:Muscle, Skeletal / Q000378:metabolism*; D009570:Nitriles; D011292:Premedication
chemical_list: D002396:Catechols; D009570:Nitriles; D007980:Levodopa; C071192:entacapone; D002230:Carbidopa