Comparative Pharmacokinetics of Free Muramyl Tripeptide Phosphatidyl Ethanolamine (MTP-PE) and Liposomal MTP-PE

Abstract

□ The comparative pharmacokinetics of free MTP-PE (muramyl tripeptide phosphatidyl ethanolamine) and MTP-PE entrapped in negatively charged multilamellar liposomes (liposomal MTP-PE) was evaluated in rats at a bolus intravenous (iv) dose of 0.2 mg/kg and in dogs at a bolus iv dose of 0.1 mg/kg. Additional studies were performed with the free form in rats (1.4 mg/kg, bolus iv) and dogs (1 mg/kg, bolus iv) and with the liposomal form in dogs (0.5 mg/kg, bolus iv). Plasma samples were obtained at various times up to 48h postinjection and assayed for the drug by a chemiluminescence immunoassay. The pharmacokinetic data regarding liposomal MTP-PE describe the distribution of free drug released from liposomes and total drug concentrations. The present studies demonstrate that the distribution characteristics of MTP-PE changed dramatically depending on the dosage form. The elimination kinetics of free MTP-PE from blood is substantially slower than that of the liposomal drug. For liposomal MTP-PE, free drug levels in plasma are very low compared with free MTP-PE. In rats at a dose of 0.2mg/kg, 96% of MTP-PE contained in liposomes is removed from the plasma compartment 10min after injection, and in dogs at a dose of 0.1 mg/kg, 100% of MTP-PE contained in liposomes is removed in the same time period. This rapid phase of liposome clearance is followed by a slower rate of clearance for the remainder of the liposomes in rats at a dose of 0.2 mg/kg and in dogs at a dose of 0.5 mg/kg.