Distribution kinetics of a micelle-forming block copolymer Pluronic P85.
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.
Batrakova
Elena V
EV
College of Pharmacy, Department of Pharmaceutical Sciences, 986025 Nebraska Medical Center, Omaha, NE 68198-6025, USA.
Li
Shu
S
Li
Yili
Y
Alakhov
Valery Yu
VY
Elmquist
William F
WF
Kabanov
Alexander V
AV
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004339:Drug Compounding; D005079:Excipients / Q000493:pharmacokinetics; D005260:Female; D006207:Half-Life; D051379:Mice; D008810:Mice, Inbred C57BL; D008823:Micelles; D011060:Poloxalene / Q000737:chemistry / Q000493:pharmacokinetics*; D011485:Protein Binding; D014018:Tissue Distribution
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001798:Blood Proteins; D005079:Excipients; D008823:Micelles; C422648:pluronic block copolymer p85; D011060:Poloxalene