Pharmacokinetic characterization of phosphatidylserine liposomes in the rat.

1. The plasma decay, tissue uptake and biotransformation of radiolabelled phosphatidylserine (PS) liposomes have been investigated in rats following bolus i.v. injection (2 mg kg-1). 2. PS plasma concentration showed a biexponential decay with half-lives of 0.85 and 40 min. The following interpretation of the biphasic decay is proposed: (1) The rapid initial decline is due to the irreversible uptake of PS liposomes by the mononuclear phagocyte system, as demonstrated by the almost exclusive accumulation of PS in liver and spleen. (2) The slow decay phase reflects the elimination of that fraction of PS that has been incorporated into high density plasma lipoproteins (HDL). A kinetic model has been developed to describe these phenomena and a good agreement has been observed between experimental data and theoretical values. 3. Evidence has been obtained that a large fraction of PS is hydrolyzed at the injection site, probably by phospholipase A2 and other hydrolytic enzymes released by platelets. Hydrolysis at the injection site has also been observed following intraperitoneal and intramuscular injections. 4. As shown by the comparative analysis of the biotransformation products found in tissues after administration of either [3H]-glycerol-PS or [14C]-serine-PS, parenterally administered PS follows two distinct metabolic pathways: (1) decarboxylation to phosphatidylethanolamine and (2) extensive hydrolytic degradation with release of the individual components of the molecule. These pathways probably reflect the two main mechanisms of PS uptake, incorporation into the plasma membrane and internalization by endocytosis, respectively.