Cremophor reduces paclitaxel penetration into bladder wall during intravesical treatment

Purpose: We have previously shown that paclitaxel, when dissolved in water and instilled into the bladder, readily penetrates the urothelium. The FDA- approved formulation uses Cremophor and ethanol to dissolve paclitaxel. In the present study, the effects of this solvent system on the urine, bladder tissue, and plasma pharmacokinetics of intravesical paclitaxel were evalua ted. Methods: Plasma, urine, and tissue pharmacokinetics were determined in five dogs treated for 120 min with paclitaxel (500 mu g per 20 ml of 0.22% w/v Cremophor and 0.21% v/v ethanol) by intravesical instillation. Equilib rium dialysis was used to determine the free fraction of paclitaxel and the presence of Cremophor micelles was verified using a fluorescent probe meth od. Results: The average bladder tissue concentration was >1600-fold higher than the plasma concentration. Comparison of the results for paclitaxel di ssolved in Cremophor/ethanol with our previous results of paclitaxel dissol ved in water (500 mu g per 20 ml) indicates that Cremophor/ethanol decrease d the paclitaxel partition across the urothelium and reduced the average bl adder tissue concentration by 75%, but did not alter the rate of paclitaxel penetration across the bladder wall, the urine pharmacokinetics or the pla sma pharmacokinetics of paclitaxel. For Cremophor, the urine concentrations during the 120-min treatment ranged from 0.12% to 0.22%, and the concentra tion in bladder tissue from 0.00004% to 0.0009%. The threshold Cremophor co ncentration for micelle formation was 0.008%. We found that ethanol at conc entrations up to 1% and Cremophor at concentrations below 0.01% did not alt er the free fraction of paclitaxel, whereas Cremophor at higher concentrati ons, i.e. 0.065% and 0.25%, significantly reduced the free fraction by two- to six-fold, respectively. These results indicate that during intravesical instillation of the FDA-approved paclitaxel formulation, the concentration of Cremophor in urine was sufficient to form micelles, resulting in seques tration of paclitaxel into micelles, reduction in the free fraction of pacl itaxel and consequently a reduction in paclitaxel penetration across the ur othelium. In contrast, the Cremophor concentrations in bladder tissue were inadequate to form micelles and thus did not alter the drug penetration thr ough the bladder tissue. Conclusions: We conclude that intravesical paclita xel treatment using the FDA-approved formulation provides a significant bla dder tissue targeting advantage, although the advantage is lower than when paclitaxel is dissolved in water.