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 (Cmax = 4.8 ± 1.10 μg/ml at 2 min), whereas oral administration of l-dopa produced a much delayed and lower Cmax (1.8 ± 0.40 μg/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.
Footnotes
-
DOI: 10.1124/jpet.103.064121.
-
ABBREVIATIONS: PD, Parkinson's disease; 6-OHDA, 6-hydroxydopamine; DOPAC, dihydroxyphenylacetic acid; ANOVA, analysis of variance; CMC, carboxymethylcellulose.
- Accepted March 18, 2004.
- Received December 15, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|