PT  - JOURNAL ARTICLE
AU  - Brouwer, Eric
AU  - Verweij, Jaap
AU  - De Bruijn, Peter
AU  - Loos, Walter J.
AU  - Pillay, Marrimuthoo
AU  - Buijs, Dirk
AU  - Sparreboom, Alex
TI  - Measurement of Fraction Unbound Paclitaxel in Human Plasma
DP  - 2000 Oct 01
TA  - Drug Metabolism and Disposition
PG  - 1141--1145
VI  - 28
IP  - 10
4099  - http://dmd.aspetjournals.org/content/28/10/1141.short
4100  - http://dmd.aspetjournals.org/content/28/10/1141.full
SO  - Drug Metab Dispos2000 Oct 01; 28
AB  - 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. The American Society for Pharmacology and Experimental Therapeutics