MICRODIALYSIS STUDY OF ZIDOVUDINE (AZT) TRANSPORT IN RAT-BRAIN

The concentration profiles of [C-14]3'-azido-3'-deoxythymidine (AZT) e manating from an acutely implanted microdialysis probe were measured i n rat caudate putamen by quantitative autoradiography for infusions of 14 min and 1 and 2 h. A mathematical model which simulated diffusive solute transport, unaffected by the processes of microvascular exchang e or tissue metabolism, did not fit the observed concentration profile s. Chromatographic analysis of brain homogenates for metabolites of AZ T showed that the rate of metabolic transformation was not large enoug h to affect transport of the drug through the brain tissue. A model si mulating the effect of microvascular exchange on the diffusion profile s fit the observed concentration profiles and the transient change in the dialysate extraction fraction. This analysis yielded an estimated tissue elimination rate constant for microvascular exchange of K(el) = 0.01 3 ml/(g . min) and an intra- to extracellular partition coeffici ent of K(pi) = 1.04. Inclusion of probenecid in the dialysate, togethe r with an i.p. injection, led to a substantial increase in the diffusi on distance of the labeled AZT from the microdialysis probe, suggestin g at least a 4-fold decrease in the microvascular exchange rate consta nt. These results imply that AZT is actively transported out of the br ain parenchyma to the microvasculature and that this active transport mechanism is responsible for the limited central nervous system penetr ation of systemically administered AZT, in spite of its high lipid sol ubility.