HUMAN PLASMA DISTRIBUTION OF FREE PACLITAXEL AND PACLITAXEL ASSOCIATED WITH DIBLOCK COPOLYMERS

Amphiphilic diblock copolymer poly (D,L-lactide)-block-methoxy polyeth ylene glycol was synthesized, and paclitaxel (Taxol) was incorporated into this copolymer above its critical micelle concentration (cmc), re sulting in the formation of polymeric micellar paclitaxel (PMT). Free paclitaxel dissolved in acetonitrile (TAX) and PMT, at 10 mu g of pacl itaxel/mL of human plasma, were incubated for 5, 30, and 60 min at 37 degrees C. Following incubation, the plasma was separated into its hig h-density (HDL), low-density (LDL), very-low-density (VLDL) lipoprotei n and lipoprotein-deficient (LPDP) plasma fractions by density gradien t ultracentrifugation. Each of these lipoprotein (LP) and LPDP fractio ns were analyzed for paclitaxel and plasma lipid levels by well-establ ished HPLC and enzymatic assays. When TAX was incubated in human plasm a for 5 min, an equal amount of drug was found in the LP and LPDP frac tions. This distribution profile did not change following incubation f or 30 and 60 min. Of the amount of TAX that was distributed within the LP fraction, 70-75% of TAX was associated with the HDL fraction for a ll time points studied. The paclitaxel plasma and LP distribution prof ile for PMT was similar to the distribution profile of TAX, suggesting that the plasma and LP distribution of paclitaxel is independent of t he method of paclitaxel delivery and that LP distribution is not a fun ction of mass lipid levels.