EFFECT OF THE P-GLYCOPROTEIN INHIBITOR, SDZ PSC-833, ON THE BLOOD ANDBRAIN PHARMACOKINETICS OF COLCHICINE

The effect of the multidrug resistance-reversing agent, SDZ PSC 833, o n blood and brain pharmacokinetics of a P-glycoprotein substrate, colc hicine, was investigated using simultaneous blood and brain microdialy sis in freely moving rats. The use of microdialysis for pharmacokineti c studies was validated by comparing the blood concentrations of colch icine obtained by microdialysis with those obtained by direct blood sa mpling. The rats received either SDZ PSC 833 (2.3 mg/kg i.v. bolus fol lowed by 16.7 mu g/min/kg i.v. infusion during all the experiment) and colchicine (1 mg/kg i.v. bolus followed by 12.5 mu g/min/kg i.v. infu sion during 2 hours) or colchicine alone (the same dosage with SDZ PSC 833 vehicle). The SDZ PSC 833 treatment resulted in important modific ations of colchicine blood pharmacokinetics: the unbound colchicine bl ood concentration at steady-state was enhanced from 149.6 +/- 9.9 to 3 33.5 +/- 81.7 ng/ml indicating a two-fold decrease in colchicine clear ance. Moreover the coadministration of SDZ PSC 833 increased the brain penetration of colchicine by a factor of 10, at least. This enhanceme nt could not be exactly assessed because the brain dialysate concentra tions of control group were below the limit of detection. Nevertheless , the large increase of colchicine brain penetration is consistent wit h the hypothesis that SDZ PSC 833 is able to inhibit the P-glycoprotei n pump present at the blood-brain barrier.