Editors' ChoiceParkinson’s Disease

Prodrug Progress

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Science Translational Medicine  21 Dec 2011:
Vol. 3, Issue 114, pp. 114ec209
DOI: 10.1126/scitranslmed.3003584

Strategies involving prodrugs—chemically modified drug molecules that are biologically converted back to the original drug compound—are often used to improve the pharmacokinetics of a drug with limitations such as poor absorption or poor solubility. For example, L-dopa, a prodrug that is useful for treating deficiencies of the neurotransmitter dopamine that are associated with Parkinson’s disease, crosses the blood-brain barrier more easily than dopamine itself. Within the brain, decarboxylase enzymes transform L-dopa into dopamine. Nevertheless, the short plasma half-life of L-dopa can result in pulsatile stimulation of postsynaptic dopamine receptors and side effects such as variable motor response.

With the goal of providing continuous dopaminergic stimulation, D’Aurizio et al. previously developed a lipoic acid prodrug of L-dopa—that’s right, a prodrug of a prodrug. This derivative, LD-LA, both prolongs the plasma levels of L-dopa and acts as an antioxidant (a characteristic that may also prove useful in Parkinson’s disease). Despite this advance, LD-LA is still susceptible to rapid hydrolysis, so multiple daily doses would be required. Therefore, these investigators have now developed biodegradable microspheres containing LD-LA. These microspheres improve the pharmacokinetics of LD-LA in two ways: First, the microsphere encapsulation protects LD-LA from early enzymatic cleavage; second, diffusion of LD-LA from the polymer matrix of the microspheres results in a gradual release of this prodrug, thereby reducing the required dosing frequency.

When D’Aurizio and colleagues administered these microspheres subcutaneously in rats, dopamine levels in the striatum (a site of dopamine action in the brain) were sustained above 0.8 µg per mg of tissue for over 96 hours. In contrast, LD-LA alone maintained similar levels for less than 24 hours; L-dopa itself resulted in substantially lower striatal dopamine levels at all time points studied. This prolonged drug action resulting from the LD-LA prodrug microencapsulation should translate to less fluctuation in dopamine levels in the brain and, accordingly, less variation in muscular control. In vitro–in vivo correlations between microsphere release and plasma levels of LD-LA suggest great promise in the ability of such prodrug research to improve Parkinson’s disease therapy further.

E. D’Aurizio et al., Biodegradable microspheres loaded with an anti-Parkinson prodrug: An in vivo pharmacokinetic study. Mol. Pharm. 8, 2408–2415 (2011). [Abstract]

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