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

The effects of carbidopa and entacapone pretreatment on the pharmacoki netics and metabolism of i.v. administered L-3,4-dihydroxyphenylalanin e (L-dopa) have been examined in vivo in blood plasma and skeletal mus cle extracellular fluid (ECF), in beagle dog, by microdialysis, Both w ith or without carbidopa, blood plasma L-dopa levels declined biexpone ntially after the i.v. administration of L-dopa. In contrast to blood plasma, a monoexponential decline was observed in muscle ECF in both t hese pharmacological conditions. Pretreatment with carbidopa had no si gnificant effect on the pharmacokinetic parameters of L-dopa in blood plasma, but resulted in an increase in the area under the concentratio n versus time curve (AUG) and elimination half-life (t(1/2)) of L-dopa in muscle ECF (0.61 hr), compared with values achieved after L-dopa a lone. Carbidopa pretreatment enhanced the accumulation of 3-O-methyldo pa(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 b lood plasma and muscle ECF, respectively. Pretreatment with carbidopa plus entacapone enhanced the T-max of L-dopa in muscle ECF compared wi th the values achieved after pretreatment with carbidopa alone. In add ition, the elimination half-life (2.66 hr) and volume of distribution by area of L-dopa in blood plasma and its AUC and t(1/2) 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 result s suggested that carbidopa has a L-dopa-sparing effect in skeletal mus cle, which is further enhanced by entacapone.