Measurement of fraction unbound paclitaxel in human plasma

The clinical pharmacokinetic behavior of paclitaxel (Taxol) is distinctly n onlinear, with disproportional increases in systemic exposure with an incre ase in dose. We have recently shown that Cremophor EL, the formulation vehi cle 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 concentration s of Cremophor EL in the central plasma compartment. To test this hypothesi s, a reproducible equilibrium dialysis method has been developed for the me asurement of paclitaxel fu in plasma. Equilibrium dialysis was performed at 37 degrees C in a humidified atmosphere of 5% CO2 using 2.0-ml polypropyle ne test tubes. Experiments were carried out with 260-mu l aliquots of plasm a containing a tracer amount of [G-H-3] paclitaxel with high-specific activ ity against an equal volume of 0.01 M phosphate buffer (pH 7.4). Drug conce ntrations were measured by both reversed-phase HPLC and liquid scintillatio n counting. Using this method, fu has been measured in three patients recei ving 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 meth od was also used to define concentration-time profiles of unbound drug, est imated from the product of the total plasma concentration and fu.