Evaluation of rat striatal L-dopa and DA concentration after intraperitoneal administration of L-dopa prodrugs in liposomal formulations.
Parkinson's disease is a neurodegenerative disease and its symptoms are relieved by administration of L-dopa (LD), which is converted by neuronal aromatic L-aminoacid decarboxylase (AADC), restoring dopamine (DA) levels in surviving neurons. In order to minimize unfavourable side effects, we studied new dimeric LD derivatives, as potential prodrugs for Parkinson's therapeutic treatment. To improve the bioavailability of the synthesized prodrugs, they were encapsulated in unilamellar liposomes of dimiristoylphosphatidylcholine (DMPC) and cholesterol (CHOL). In vivo microdialysis was used to monitor the striatal LD and DA concentrations after i.p. administration of new delivery systems. Bioavailability evaluation was performed by means of the HPLC-EC method. The striatal levels of LD and DA were remarkably elevated after i.p. administration of liposomal formulation of prodrug (+)-1b ([(O,O-diacetyl)-L-dopa-methylester]-succinyldiamide). This formulation showed about 2.5-fold increase in the basal levels of DA in dialysate rat striatum, suggesting that liposomal formulation of (+)-1b significantly increases LD and DA concentrations with respect to equimolar administration of LD itself or free prodrug (+)-1b.
Di Stefano
Antonio
A
Dipartimento di Scienze del Farmaco, Università G. D'Annunzio, Via dei Vestini 31, 66100 Chieti, Italy. adistefano@unich.it
Carafa
Maria
M
Sozio
Piera
P
Pinnen
Francesco
F
Braghiroli
Daniela
D
Orlando
Giustino
G
Cannazza
Giuseppe
G
Ricciutelli
Massimo
M
Marianecci
Carlotta
C
Santucci
Eleonora
E
D000577:Amides / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D000978:Antiparkinson Agents / Q000737:chemistry / Q000494:pharmacology; D001682:Biological Availability; D002784:Cholesterol / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D019281:Dimerization; D004134:Dimyristoylphosphatidylcholine / Q000737:chemistry; D004298:Dopamine / Q000008:administration & dosage* / Q000737:chemistry* / Q000493:pharmacokinetics; D016503:Drug Delivery Systems / Q000379:methods; D005110:Extracellular Space / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D007274:Injections, Intraperitoneal; D007980:Levodopa / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D008081:Liposomes / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D017551:Microdialysis / Q000379:methods; D017072:Neostriatum / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism; D011355:Prodrugs / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats
C499097:((O,O-diacetyl)-L-dopa-methylester)succinyldiamide; D000577:Amides; D000978:Antiparkinson Agents; D008081:Liposomes; D011355:Prodrugs; D007980:Levodopa; D002784:Cholesterol; D004134:Dimyristoylphosphatidylcholine; D004298:Dopamine