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Vol. 27, Issue 6, 689-694, June 1999

Effect of PSC 833, a P-Glycoprotein Modulator, on the Disposition of Vincristine and Digoxin in Rats

SaeHeum Song, Hiroshi Suzuki, Ryosei Kawai, and Yuichi Sugiyama

Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan (S.H.S, H.S., Y.S.); and Department of Drug Metabolism & Pharmacokinetics, Novartis Pharma Ltd., Basel, Switzerland (R.K.)

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.

Copyright © 1999 by The American Society for Pharmacology and Experimental Therapeutics


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