Evaluation of rat striatal l-dopa and DA concentration after intraperitoneal administration of l-dopa prodrugs in liposomal formulations

• Published in: Journal of controlled release Vol. 99; no. 2; pp. 293 - 300
• Main Authors: Di Stefano, Antonio, Carafa, Maria, Sozio, Piera, Pinnen, Francesco, Braghiroli, Daniela, Orlando, Giustino, Cannazza, Giuseppe, Ricciutelli, Massimo, Marianecci, Carlotta, Santucci, Eleonora
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 30.09.2004; Elsevier
• Subjects: Amides - metabolism; Amides - pharmacology; Animals; Antiparkinson Agents - chemistry; Antiparkinson Agents - pharmacology; Biological and medical sciences; Biological Availability; Cholesterol - chemistry; Chromatography, High Pressure Liquid - methods; Dimerization; Dimyristoylphosphatidylcholine - chemistry; Dopamine - administration & dosage; Dopamine - chemistry; Dopamine - pharmacokinetics; Drug Delivery Systems - methods; Extracellular Space - chemistry; Extracellular Space - drug effects; Extracellular Space - metabolism; General pharmacology; Injections, Intraperitoneal; l-dopa; l-dopa prodrugs; Levodopa - administration & dosage; Levodopa - analogs & derivatives; Levodopa - chemistry; Levodopa - metabolism; Levodopa - pharmacokinetics; Levodopa - pharmacology; Liposomes; Liposomes - chemistry; Liposomes - metabolism; Liposomes - pharmacology; Medical sciences; Microdialysis; Microdialysis - methods; Neostriatum - chemistry; Neostriatum - drug effects; Neostriatum - metabolism; Parkinson's disease; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Prodrugs - chemistry; Prodrugs - metabolism; Prodrugs - pharmacology; Rats; l-dopa; Parkinson's disease; Microdialysis; Liposomes; l-dopa prodrugs; Agonist; Intraperitoneal administration; Rat; L-dopa; L-dopa prodrugs; Parkinson disease; Formulation; Degenerative disease; Levodopa; Evaluation; Nervous system diseases; Pharmaceutical technology; Rodentia; Liposome; Concentration; Prodrug; Antiparkinson agent; Cerebral disorder; Vertebrata; Mammalia; D2 Dopamine receptor; Animal; Central nervous system disease; Extrapyramidal syndrome
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2004.07.010

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.