Abstract

PSC 833 has been used to overcome the phenomenon of multidrug resistance by inhibiting the P-glycoprotein (P-gp)-mediated efflux of antitumor drugs from tumor cells. Because P-gp expressed in several normal tissues may affect the disposition of its substrates, we examined the dose-dependent effect of PSC 833 on the disposition of vincristine (VCR) and digoxin (DGX) in rats. One-tenth milligram per kilogram PSC 833 was sufficient to significantly reduce the biliary excretion clearance of DGX from 3.0 ml/min/kg to 0.5 ml/min/kg, whereas 3 mg/kg PSC 833 was needed to significantly reduce the biliary excretion clearance of VCR from 36 ml/min/kg to 9 ml/min/kg. Three milligrams per kilogram PSC 833 significantly reduced the renal clearance of VCR by 30% but did not affect that of DGX significantly. The tissue-to-plasma DGX concentration ratio in the brain at 6 h after administration (0.34 versus 1.64), but not that of VCR at 2 h (1.07 versus 1.37), was significantly increased by PSC 833, 3 mg/kg. The differential effect of PSC 833 on the disposition of VCR and DGX may be ascribed to the different degree of contribution of P-gp to the disposition of these ligands.