Enhancement of the systemic and CNS specific delivery of L-dopa by the nasal administration of its water soluble prodrugs.
OBJECTIVE
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 delivery method will result in preferential delivery to the CNS.


METHODS
Several alkyl ester prodrugs of L-dopa were prepared and their physicochemical properties were determined. In vitro hydrolysis rate constants in buffer, rat plasma, rat brain homogenate, rat CSF, and rat nasal berfusate 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 following nasal delivery of the prodrugs with bioavailability around 90%. Dopamine plasma levels did not change significantly following nasal administration of the butyl ester prodrug. Olfactory bulb and CSF L-dopa concentration were higher following nasal delivery of the butyl ester prodrug compared to 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 advantages such as improved bioavailability, decreased side effects, and potentially enhanced CNS delivery.
Kao
H D
HD
Endo Pharmaceuticals, Garden City, New York 11530, USA.
Traboulsi
A
A
Itoh
S
S
Dittert
L
L
Hussain
A
A
D000281:Administration, Intranasal; D000818:Animals; D000978:Antiparkinson Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D002021:Buffers; D002851:Chromatography, High Pressure Liquid; D004298:Dopamine / Q000097:blood; D004355:Drug Stability; D006207:Half-Life; D006868:Hydrolysis; D007275:Injections, Intravenous; D007980:Levodopa / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D008297:Male; D009830:Olfactory Bulb / Q000378:metabolism; D011355:Prodrugs / Q000008:administration & dosage* / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility
D000978:Antiparkinson Agents; D002021:Buffers; D011355:Prodrugs; D007980:Levodopa; D004298:Dopamine