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Research ArticleArticle

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
Drug Metabolism and Disposition June 1999, 27 (6) 689-694;
SaeHeum Song
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Hiroshi Suzuki
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Ryosei Kawai
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Yuichi Sugiyama
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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

  • 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

  • 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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Drug Metabolism and Disposition: 27 (6)
Drug Metabolism and Disposition
Vol. 27, Issue 6
1 Jun 1999
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Research ArticleArticle

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
Drug Metabolism and Disposition June 1, 1999, 27 (6) 689-694;

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Research ArticleArticle

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
Drug Metabolism and Disposition June 1, 1999, 27 (6) 689-694;
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