EVALUATION OF A BRAIN-TARGETING ZIDOVUDINE CHEMICAL DELIVERY SYSTEM IN DOGS

AIDS encephalopathy is an insidious complication of human immunodefici ency virus infection which is difficult to treat because of the poor u ptake of many potentially useful antiretroviral drugs through the bloo d-brain barrier. A chemical delivery system (CDS) for zidovudine (AZT) based on redox trapping within the brain has been prepared and tested in several animal models to circumvent this limitation. The behavior of the AZT-CDS in the dog was considered, Parenteral administration of AZT resulted in rapid systemic elimination and poor uptake by the cen tral nervous system, Ratios of the area under the concentration-time c urve of AZT for cerebrospinal fluid to that for blood were 0.32, and r atios of the area under the concentration-time curve of AZT for brain to that for blood were approximately 0.25. Administration of an aqueou s formulation of the AZT-CDS resulted in rapid tissue uptake and conve rsion of the CDS to the corresponding quaternary salt with the subsequ ent production of AZT, Delivered in this way, the levels of AZT in bra in were 1.75- to 3.3-fold higher than those associated with convention al AZT administration. In additional the levels of AZT in blood were 4 6% lower than those associated with AZT administration, The higher con centrations in brain and lower concentrations in blood combined to sig nificantly increase the ratio of the concentration of AZT in the brain to that in blood after AZT-CDS administration compared to that after AZT dosing.