A pulmonary formulation of L-dopa enhances its effectiveness in a rat model of Parkinson's disease.

Abstract

The efficacy of oral L-dopa becomes problematic with the progression of Parkinson's disease, due in large part to a lost ability to accommodate L-dopa's inherently poor pharmacokinetics. Pulmonary delivery represents a novel approach to reducing this problem. L-dopa was formulated into inhalable (Alkermes AIR) particles, and its pharmacokinetics and pharmacodynamics compared with those of an oral formulation. Pulmonary administration of L-dopa (2 mg) to rats resulted in a rapid elevation of plasma levels (C(max) = 4.8 +/- 1.10 microg/ml at 2 min), whereas oral administration of L-dopa produced a much delayed and lower C(max) (1.8 +/- 0.40 microg/ml at 30 min). In a rat model of Parkinson's disease (unilateral 6-hydroxydopamine lesion), the pulmonary formulation of L-dopa (0.5-2.0 mg) yielded more rapid and robust elevations in striatal L-dopa, dopamine, and dihydroxyphenylacetic acid levels, as well as 2.5 to 3.7 times as many c-fos-expressing striatal neurons. Moreover, motor function was significantly improved by 10 min after administration, with peak improvements occurring within 15 to 30 min. In contrast, considerably higher doses (6.8-10 mg) of orally administered L-dopa took over three times longer to produce similar effects. These results suggest that an inhalable formulation of l-dopa has superior pharmacokinetic properties and may provide patients with a more effective form of rescue therapy as well as being a reliable adjuvant or replacement for first-line oral therapy.

• Authors: Raymond T Bartus, Dwaine Emerich, Pam Snodgrass-Belt, Karen Fu, Heather Salzberg-Brenhouse, Denise Lafreniere, Leah Novak, Ee-Sing Lo, Thomas Cooper, Anthony S Basile
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 310 Issue 2 Pg. 828-35 (Aug 2004) ISSN: 0022-3565 [Print] United States
• PMID: 15039453 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Levodopa

Topics

• Administration, Inhalation
• Animals
• Chemistry, Pharmaceutical
• Corpus Striatum (drug effects, metabolism)
• Disease Models, Animal
• Levodopa (administration & dosage, pharmacokinetics, pharmacology)
• Male
• Parkinson Disease (drug therapy, metabolism)
• Rats
• Rats, Sprague-Dawley