Transport of alovudine (3 '-fluorothymidine) into the brain and the cerebrospinal fluid of the rat, studied by microdialysis

Extracellular unbound concentrations of alovudine were sampled by microdial ysis in order to study the transport of alovudine between the blood and the brain and the cerebrospinal fluid (CSF) in the rat. The AUC (area under th e curve) ratio CSF/blood was higher than the brain/blood ratio after i.v. i nfusion of alovudine 25mg/kg/hr after a loading dose of 25 mg/kg in 5 minut es (n=4). Neither i.v. infusion of thymidine (25 mg/kg/hr, n=5; 100 mg/kg/h r, n=2) nor acetazolamide (50 mg/kg i.p. bolus followed by 25 mg/kg i.p. ev ery second hour, n=3) influenced the brain/blood AUC ratio after alovudine 25 mg/kg s.c, injection compared to controls (n=5). Finally, perfusion thro ugh the microdialysis probe with thymidine (1000 mu M, n=3) had also no eff ect on the brain/blood AUC ratio after alovudine 25 mg/kg s.c. Because neit her thymidine nor acetazolamide has significant influence on the ability of alovudine to penetrate the blood-brain barrier in the rat, neither thymidi ne transport nor carboanhydrase dependent CSF production appear to be major determinants of the blood-brain concentration gradient. Thus, it is conclu ded that alovudine reaches the extracellular fluid of the brain not by cere brospinal fluid, but via the cerebral capillaries and that the existence of a concentration gradient over both blood-brain and CSF-brain barrier can p robably be explained by the presence of an active process pumping alovudine out from the brain.