PT  - JOURNAL ARTICLE
AU  - SaeHeum Song
AU  - Hiroshi Suzuki
AU  - Ryosei Kawai
AU  - Yuichi Sugiyama
TI  - Effect of PSC 833, a P-Glycoprotein Modulator, on the Disposition of Vincristine and Digoxin in Rats
DP  - 1999 Jun 01
TA  - Drug Metabolism and Disposition
PG  - 689--694
VI  - 27
IP  - 6
4099  - http://dmd.aspetjournals.org/content/27/6/689.short
4100  - http://dmd.aspetjournals.org/content/27/6/689.full
SO  - Drug Metab Dispos1999 Jun 01; 27
AB  - 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. The American Society for Pharmacology and Experimental Therapeutics