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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Kinetics of P-Glycoprotein-Mediated Efflux of Paclitaxel

Seong Hoon Jang, M. Guillaume Wientjes and Jessie L.-S. Au
Journal of Pharmacology and Experimental Therapeutics September 2001, 298 (3) 1236-1242;
Seong Hoon Jang
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M. Guillaume Wientjes
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Jessie L.-S. Au
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Abstract

Paclitaxel is a substrate of the mdr1 P-glycoprotein (Pgp). The objective of the present study was to determine the kinetics of the Pgp-mediated efflux and its contribution to the overall efflux of paclitaxel at the clinically achievable concentration range of 1 to 1500 nM. Human breast carcinoma BC19 cells that were derived from MCF7 cells by mdr1 transfection and show a >10-fold higher level of the Pgp protein were used to measure the uptake and efflux of [3H]paclitaxel. A computational model of intracellular paclitaxel pharmacokinetics was developed to analyze for the Pgp efflux parameters. The results show a saturable Pgp-mediated efflux in BC19 cells; the dissociation constant was 14 nM, and the maximal efflux rate was 2.8 × 10−4 pmol/h/cell. The contribution of Pgp-mediated efflux to the total efflux decreased with increasing extracellular drug concentrations; the Pgp efflux accounted for 86 and 34% of total efflux at 1 and 1500 nM, respectively. The validity of the model was confirmed by the close agreement between the model-predicted data and the experimentally obtained data (∼6% deviation) describing the effect of cell density and intracellular-to-extracellular concentration gradient on the kinetics of drug accumulation and efflux. In conclusion, our results indicate that the Pgp-mediated efflux represents a major efflux mechanism of paclitaxel at the low end of the clinically observed drug concentration range, but accounts for only a minor part of the efflux at higher concentrations in BC19 cells.

Footnotes

  • This work was partially supported by Research Grants R37CA49816 and R01CA63363 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services.

  • Abbreviations:
    Pgp
    P-glycoprotein
    Jmax and KM,Pgp
    maximum rate and dissociation constant of Pgp-mediated efflux, respectively
    Ctotal,c and Ctotal,m
    total drug concentrations (i.e., free plus bound) in cells and medium, respectively
    Cfree,c and Cfree,m
    free drug concentrations in cells and medium, respectively
    Vc
    volume of cells
    CLf,d and CLPgp
    clearance of free drug by passive diffusion and Pgp efflux, respectively
    Bmax,c and Bmax,m
    maximum drug binding capacity in cells and medium, respectively
    Kd,c and Kd,m
    dissociation constants for drug binding to saturable binding sites in cells and medium, respectively
    NSB
    proportionality constant for nonsaturable binding in cells
    Vone cell
    mean volume of a single cell
    ICN
    initial cell number at time 0
    kcell number
    rate constant for changes in cell number
    kBmax,c
    rate constant for increase inBmax,c
    Bmax,c(t) and Bmax,c,initial
    Bmax,c at time t and 0, respectively
    • Received February 26, 2001.
    • Accepted May 1, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 298 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 298, Issue 3
1 Sep 2001
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Kinetics of P-Glycoprotein-Mediated Efflux of Paclitaxel

Seong Hoon Jang, M. Guillaume Wientjes and Jessie L.-S. Au
Journal of Pharmacology and Experimental Therapeutics September 1, 2001, 298 (3) 1236-1242;

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Kinetics of P-Glycoprotein-Mediated Efflux of Paclitaxel

Seong Hoon Jang, M. Guillaume Wientjes and Jessie L.-S. Au
Journal of Pharmacology and Experimental Therapeutics September 1, 2001, 298 (3) 1236-1242;
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