Microdialysis was used to sample extracellular unbound concentrations of alovudine in order to study the influence of well-known transport inhibitors (probenecid and quinidine) on the transport of alovudine between the blood and the brain extracellular fluid or whole brain tissue. The AUC (area under the time versus concentration curve) ratio brain extracellular fluid/serum was 0.17+/-0.036 after a subcutaneous injection of alovudine 25 mg/kg in rats treated with probenecid 25 mg/kg subcutaneous (n=5), which was not significantly different from the control group (AUC ratio 0.24+/-0.039). Perfusion through the microdialysis probe with probenecid 100 microM (n=4) also had no effect on the brain extracellular fluid/serum AUC ratio after alovudine 25 mg/kg subcutaneous. The AUC ratio brain extracellular fluid/serum was 0.085+/-0.009 after subcutaneous injection of alovudine 25 mg/kg in rats treated with quinidine 25 mg/kg intraperitoneally (n=8), which was significantly lower than the control group. However, the whole brain tissue concentration was not significantly different between control rats (n=5) and rats treated with quinidine (n=4) 1 hr after subcutaneous injection of alovudine 25 mg/kg (brain to serum ratios being 0.11+/-0.006 and 0.10+/-0.005 respectively). Finally, the microdialysis recovery of alovudine increased with increasing concentrations (10, 50, 250, 1250 microM) of alovudine in the perfusion fluid. The recovery of alovudine was increased in quinidine-treated rats but not in those given probenecid. Thus, probenecid does not significantly influence the concentration gradient of alovudine over the blood-brain barrier in the rat after systemic or after local administration, while quinidine lowered brain extracellular fluid concentration of alovudine, but not total brain tissue concentration. The mechanism behind this phenomenon is not yet known.