Improved brain delivery of AZT using a glycosyl phosphotriester prodrug

Abstract

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.

Pharmacology of Brain Na+/Ca2+Exchanger: From Molecular Biology to Therapeutic Perspectives

“…3). By virtue of this strategy, the peptide more easily penetrates into the cell, since the glucose molecule, actively transported into the cell through the glucose transporters (glucose transporters 1 and 3), carries the attached peptide (Namane et al, 1992). Interestingly, this Tyr-6-glycosilated form of XIP (Fig.…”

Glycopeptide enkephalin analogues produce analgesia in mice: evidence for penetration of the blood-brain barrier.

“…A number of polar metabolites required by the brain are actively transported into the brain, either by receptor-mediated endocytosis (13) or by gradient-driven cotransport systems (14). For example, researchers have demonstrated improved delivery of 3'-azido-3'-deoxythymidine (AZT) to the brain by using a glycosyl phosphotriester derivative of the drug, which is presumably transported by a nucleoside transporter (15 (19,20 (21). In that study, with centrally (i.c.v.)…”

Novel Nucleoside Phosphoramidates as Inhibitors of HIV: Studies on the Stereochemical Requirements of the Phosphoramidate Amino Acid

“…In an attempt to improve on the therapeutic potential of current antiviral nucleoside analogues there have been reports on a variety of masked monophosphate derivatives, designed to act as membrane-soluble pro-drugs of the bio-active phosphate forms (Farrow et al, 1990;McGuigan et el., 1990aMcGuigan et el., ,b,c, 1991McGuigan et el., , 1992Henin et al, 1991;Namane et al, 1992;Dessaux and Huynh-Dinh, Received22 February,1996;revised4 March,1996;accepted18 March,1996. *For correspondence.…”