PROLONGATION OF THE CIRCULATION TIME OF DOXORUBICIN ENCAPSULATED IN LIPOSOMES CONTAINING A POLYETHYLENE GLYCOL-DERIVATIZED PHOSPHOLIPID - PHARMACOKINETIC STUDIES IN RODENTS AND DOGS

The pharmacokinetics of doxorubicin (DOX) encapsulated in liposomes co ntaining polyethylene glycol-derivatized distearoylphosphatidylethanol amine (PEG/DSPE) were investigated in rodents and dogs. The plasma lev els of DOX obtained with PEG/DSPE-containing liposomes were consistent ly higher than those without PEG/DSPE or when PEG/DSPE was replaced wi th hydrogenated phosphatidylinositol (HPI). Despite the inclusion of P EG/DSPE in liposomes, there was a significant drop in the plasma level s of DOX when the main phospholipid component, hydrogenated phosphatid ylcholine, was replaced with lipids of lower phase transition temperat ure (dipalmitoylphosphatidylcholine, egg phosphatidylcholine), indicat ing that phase transition temperature affects the pharmacokinetics of liposome-encapsulated DOX. In beagle dogs, clearance was significantly slower for DOX encapsulated in PEG/DSPE-containing liposomes than in HPI-containing liposomes, with distribution half-lives of 29 and 13 hr , respectively. In both instances, almost 100% of the drug measured in plasma was liposome-associated. The apparent volume of distribution w as only slightly above the estimated plasma volume of the dogs, indica ting that drug leakage from circulating liposomes is insignificant and that the distribution of liposomal drug is limited mostly to the intr avascular compartment in health animals.