Pluronic block copolymers, micelle-forming polymeric surfactants, are currently being evaluated in chemotherapy clinical trials in combination with doxorubicin to treat multidrug-resistant (MDR) tumors. This study examines the pharmacokinetics and biodistribution of Pluronic P85 (P85), a potent inhibitor of P-glycoprotein (Pgp). P85 was radioactively labeled and administered intravenously (i.v.) to mice. The concentration of the copolymer was varied to examine the effects of micelle formation on the distribution kinetics. The main pharmacokinetic parameters (the area under the curve, half-life, clearance, mean residence time, and volume of distribution) were determined. The results suggest that half-life of P85 varies from 60 to 90 h, depending on its aggregation state. Formation of micelles decreased the uptake of the block copolymer in the liver. However, it had no effect on the total clearance, suggesting that the elimination of P85 was controlled by the renal elimination of P85 unimers and not by the rate of micelle disposition or disintegration. The total clearance value suggests that a significant portion of P85 is reabsorbed back into the blood, probably through the kidney's tubular membranes.
Bibliographical noteFunding Information:
This study was supported by National Institutes of Health grants to AVK (NS36229, CA89225) and WFE (NS42549).