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 degrees C in a humidified
atmosphere of 5% CO(2) using 2.0-ml polypropylene test tubes. Experiments
were carried out with 260-microliter aliquots of plasma containing a
tracer amount of [G-(3)H]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/m(2) 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