Human red blood cells as bioreactors for the release of 2',3'-dideoxycytidine, an inhibitor of HIV infectivity.
2',3'-Dideoxycytidine (ddCyd) is one of the most potent antiviral nucleosides for killing the human immunodeficiency virus (HIV). ddCyd is currently used in the treatment of severe HIV infections but due to its rapid clearance it must be administered to patients every 4 h reaching concentrations that are toxic. We have synthesized 2',3'-dideoxycytidine-5'-phosphate (ddCMP) as a prodrug, encapsulated it in human erythrocytes and found that it is dephosphorylated by endogenous pyrimidine nucleotidases and subsequently released by the cells as ddCyd. Encapsulated ddCMP does not affect erythrocyte metabolism and was not deaminated by cytidine deaminase. The dephosphorylation reaction has an apparent Km of 6mM, an optimum pH of 6.8 and is not inhibited by ATP or 2,3-bisphosphoglycerate. The efflux of ddCyd from the erythrocyte is a linear function of ddCyd concentration and relatively insensitive to nucleoside transporter inhibitors suggesting that ddCyd permeates the erythrocyte membrane predominantly by nonfacilitated diffusion. Thus, ddCMP-loaded erythrocytes might be used as endogenous bioreactors for ddCyd delivery in the treatment of HIV infection.
Magnani
M
M
Instituto di Chimica Biologica, Università degli Studi, Urbino, Italy.
Bianchi
M
M
Rossi
L
L
Stocchi
V
V
D004333:Drug Administration Routes; D004912:Erythrocytes / Q000378:metabolism*; D006678:HIV / Q000187:drug effects*; D006801:Humans; D010766:Phosphorylation; D016047:Zalcitabine / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000493:pharmacokinetics
D016047:Zalcitabine