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Rapid CommunicationShort Communication

Measurement of Fraction Unbound Paclitaxel in Human Plasma

Eric Brouwer, Jaap Verweij, Peter De Bruijn, Walter J. Loos, Marrimuthoo Pillay, Dirk Buijs and Alex Sparreboom
Drug Metabolism and Disposition October 2000, 28 (10) 1141-1145;
Eric Brouwer
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Jaap Verweij
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Peter De Bruijn
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Walter J. Loos
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Marrimuthoo Pillay
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Dirk Buijs
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Alex Sparreboom
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Abstract

The clinical pharmacokinetic behavior of paclitaxel (Taxol) is distinctly nonlinear, with disproportional increases in systemic exposure with an increase in dose. We have recently shown that Cremophor EL, the formulation vehicle used for i.v. administration of paclitaxel, alters drug distribution as a result of micellar entrapment of paclitaxel, and we speculated that the free drug fraction (fu) is dependent on dose and time-varying concentrations of Cremophor EL in the central plasma compartment. To test this hypothesis, a reproducible equilibrium dialysis method has been developed for the measurement of paclitaxel fu in plasma. Equilibrium dialysis was performed at 37°C in a humidified atmosphere of 5% CO2 using 2.0-ml polypropylene test tubes. Experiments were carried out with 260-μl aliquots of plasma containing a tracer amount of [G-3H]paclitaxel with high-specific activity against an equal volume of 0.01 M phosphate buffer (pH 7.4). Drug concentrations were measured by both reversed-phase HPLC and liquid scintillation counting. Using this method, fu has been measured in three patients receiving three consecutive 3-weekly courses of paclitaxel at dose levels of 135, 175, and 225 mg/m2 and found to range between 0.036 and 0.079. The method was also used to define concentration-time profiles of unbound drug, estimated from the product of the total plasma concentration and fu.

Footnotes

  • Send reprint requests to: Alex Sparreboom, Ph.D., Department of Medical Oncology, Rotterdam Cancer Institute (Daniel den Hoed Kliniek) and University Hospital Rotterdam, P.O. Box 5201, 3008 AE Rotterdam, The Netherlands. E-mail: sparreboom{at}onch.azr.nl

  • Abbreviations used are::
    CrEL
    Cremophor EL
    fu
    fraction unbound
    Cp
    total plasma concentration
    Cu
    unbound concentration
    AUC
    area under the concentration versus time curve
    CL
    clearance
    • Received January 11, 2000.
    • Accepted June 28, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 28 (10)
Drug Metabolism and Disposition
Vol. 28, Issue 10
1 Oct 2000
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Rapid CommunicationShort Communication

Measurement of Fraction Unbound Paclitaxel in Human Plasma

Eric Brouwer, Jaap Verweij, Peter De Bruijn, Walter J. Loos, Marrimuthoo Pillay, Dirk Buijs and Alex Sparreboom
Drug Metabolism and Disposition October 1, 2000, 28 (10) 1141-1145;

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Rapid CommunicationShort Communication

Measurement of Fraction Unbound Paclitaxel in Human Plasma

Eric Brouwer, Jaap Verweij, Peter De Bruijn, Walter J. Loos, Marrimuthoo Pillay, Dirk Buijs and Alex Sparreboom
Drug Metabolism and Disposition October 1, 2000, 28 (10) 1141-1145;
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