Improved brain delivery of AZT using a glycosyl phosphotriester prodrug.
The concentration of AZT in mice plasma and brain was measured using HPLC after an ingestion of 20 mg/kg of AZT or the molar equivalent of hexadecyl 2-(alpha-D-mannopyranosidyl)ethyl 3'-azido-3'-deoxy-5'-thymidinyl phosphate 3. The results demonstrated the promising qualities of the prodrug 3 which gave AZT-5'-phosphate as the main metabolite: the total concentration of AZT derivatives detected in brain presented a peak of 156 nmol/g (5 nmol/g for AZT) at 1 h; the half-life was about 24 h (1 h for AZT) with an AUC of 4366 nmol h/g as compared to 4 nmol h/g for AZT. The lipophilic properties of 3 were confirmed by its in vitro transport of inside synaptosomes. The derivative 2-(alpha-D-mannopyranosidyl)ethyl 3'-azido-3'-deoxy-5'-thymidinyl phosphate (2) provided also a good delivery of AZT to the central nervous system, with values intermediate between those of AZT and 3.
Namane
A
A
Unité de Chimie Organique, URA CNRS 487, Institut Pasteur, Paris, France.
Gouyette
C
C
Fillion
M P
MP
Fillion
G
G
Huynh-Dinh
T
T
D000818:Animals; D001921:Brain / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D004952:Esters / Q000493:pharmacokinetics; D006207:Half-Life; D008297:Male; D051379:Mice; D011355:Prodrugs / Q000493:pharmacokinetics*; D013574:Synaptosomes / Q000378:metabolism; D015215:Zidovudine / Q000031:analogs & derivatives / Q000493:pharmacokinetics*
D004952:Esters; D011355:Prodrugs; D015215:Zidovudine