Song S, Suzuki H, Kawai R, Sugiyama Y
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Drug Metab Dispos. 1999 Jun;27(6):689-94.
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.
PSC 833已被用于通过抑制P-糖蛋白（P-gp）介导的抗肿瘤药物从肿瘤细胞的外排来克服多药耐药现象。由于在几种正常组织中表达的P-gp可能会影响其底物的处置，我们研究了PSC 833对大鼠长春新碱（VCR）和地高辛（DGX）处置的剂量依赖性影响。每千克0.1毫克的PSC 833足以将DGX的胆汁排泄清除率从3.0毫升/分钟/千克显著降低至0.5毫升/分钟/千克，而需要每千克3毫克的PSC 833才能将VCR的胆汁排泄清除率从36毫升/分钟/千克显著降低至9毫升/分钟/千克。每千克3毫克的PSC 833可使VCR的肾清除率显著降低30%，但对DGX的肾清除率没有显著影响。每千克3毫克的PSC 833可使给药后6小时大脑中组织与血浆的DGX浓度比（0.34对1.64）显著升高，但对2小时时VCR的浓度比（1.07对1.37）没有显著影响。PSC 833对VCR和DGX处置的差异作用可能归因于P-gp对这些配体处置的贡献程度不同。
