Hd. Kao et al., Enhancement of the systemic and CNS specific delivery of L-dopa by the nasal administration of its water soluble prodrugs, PHARM RES, 17(8), 2000, pp. 978-984
Purpose. To study the utility of the nasal route for the systemic delivery
of L-dopa using water soluble prodrugs of L-dopa and to examine if this del
ivery method will result in preferential delivery to the CNS.
Methods. Several alkyl ester prodrugs of L-dopa were prepared and their phy
sicochemical properties were determined. In vitro hydrolysis rate constants
in buffer, rat plasma, rat brain homogenate, rat CSF, and rat nasal berfus
ate were determined by HPLC. In vivo nasal experiments were carried out in
rats. Levels of L-dopa and dopamine in plasma, CSF, and olfactory bulb were
determined using HPLC method with electrochemical detection.
Results. All the prodrugs showed improved solubility and lipophilicity with
relatively fast in vitro conversion in rat plasma. Absorption was fast fol
lowing nasal delivery of the prodrugs with bioavailability around 90%. Dopa
mine plasma levels did not change significantly following nasal administrat
ion of the butyl eater prodrug. Olfactory bulb and CSF L-dopa concentration
were higher following nasal delivery of the butyl ester prodrug compared t
o an equivalent intravenous dose.
Conclusions. Utilization of water soluble prodrugs of L-dopa via the nasal
route in the treatment of Parkinson's disease may have therapeutic advantag
es such as improved bioavailability, decreased side effects, and potentiall
y enhanced CNS delivery.