The effect of the multidrug resistance-reversing agent, SDZ PSC 833, on blood and brain pharmacokinetics of a P-glycoprotein substrate, colchicine, was investigated using simultaneous blood and brain microdialysis in freely moving rats. The use of microdialysis for pharmacokinetic studies was validated by comparing the blood concentrations of colchicine obtained by microdialysis with those obtained by direct blood sampling. The rats received either SDZ PSC 833 (2.3 mg/kg i.v. bolus followed by 16.7 microg/min/kg i.v. infusion during all the experiment) and colchicine (1 mg/kg i.v. bolus followed by 12.5 microg/min/kg i.v. infusion during 2 hours) or colchicine alone (the same dosage with SDZ PSC 833 vehicle). The SDZ PSC 833 treatment resulted in important modifications of colchicine blood pharmacokinetics: the unbound colchicine blood concentration at steady-state was enhanced from 149.6 +/- 9.9 to 333.5 +/- 81.7 ng/ml indicating a two-fold decrease in colchicine clearance. Moreover the coadministration of SDZ PSC 833 increased the brain penetration of colchicine by a factor of 10, at least. This enhancement could not be exactly assessed because the brain dialysate concentrations of control group were below the limit of detection. Nevertheless, the large increase of colchicine brain penetration is consistent with the hypothesis that SDZ PSC 833 is able to inhibit the P-glycoprotein pump present at the blood-brain barrier.