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.
Footnotes
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Send reprint requests to: Dr. Yuichi Sugiyama, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7–3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. E-mail:sugiyama{at}seizai.f.u-tokyo.ac.jp
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This work was supported in part by a grant-in-aid from the Ministry of Education, Science, Sports, and Culture of Japan and Core Research for Evolutional Sciences and Technology of Japan Science and Technology Corporation.
- Abbreviations used are::
- MDR
- multidrug resistance
- P-gp
- P-glycoprotein
- VCR
- vincristine
- DGX
- digoxin
- CsA
- cyclosporin A
- AUC
- area under the plasma concentration-time curve
- Xbile
- amount of the ligand excreted into the bile
- Xurine
- amount of the ligand excreted into the urine
- CLbile
- biliary clearance
- CLR
- urinary clearance
- SD
- Sprague-Dawley
- Kp
- tissue-to-plasma concentration ratio
- Received June 23, 1998.
- Accepted February 10, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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