DISTRIBUTION OF FREE AND LIPOSOMAL ANNAMYCIN WITHIN HUMAN PLASMA IS REGULATED BY PLASMA TRIGLYCERIDE CONCENTRATIONS BUT NOT BY LIPID TRANSFER PROTEIN

Annamycin (Ann) is a lipophilic and non-cross-resistant anthracycline antibiotic currently in clinical development as a liposomal formulatio n (L-Ann) composed of dimyristoylphosphatidylcholine (DMPC) and dimyri stoylphosphatidylglycerol (DMPG). Previous studies have demonstrated t hat the incorporation of Ann into these liposomes prolongs its termina l serum half-life and increases the tumor levels of the drug. However, an explanation for the altered pharmacokinetics and pharmacodynamics of doxorubicin and Ann when entrapped into these multilamellar lipid v esicles remains unknown. Since the distribution of lipophilic compound s within plasma lipoproteins has been shown to influence the pharmacok inetics and organ distribution of a number of lipophilic compounds and this distribution appears to be regulated by lipid transfer protein ( LTP), we studied the distribution of Ann and L-Ann among plasma lipopr oteins and the influence of LTP on the distribution of Ann and L-Ann a mong plasma lipoproteins. Our results concluded that when Ann was inco rporated into liposomes composed of DMPC and DMPG, over 65% of the ini tial Ann concentration would distribute into the high density lipoprot ein (HDL) fraction and that free Ann and L-Ann distribution within hum an plasma was independent of LTP activity. In addition, we observed th at the increase in total plasma triglyceride (TG) concentrations (thro ugh the increase of very low-density lipoproteins (VLDL)) resulted in the increase distribution of Ann and L-Ann within the TG-rich VLDL fra ction. However, increasing the VLDL core TG/cholesterol ratio decrease d Ann distribution into VLDL. These findings suggest that initial Ann distribution is regulated by a mechanism that does not involve LTP, bu t through its interaction with plasma VLDL-TG. Since many cancer patie nts exhibit lipid disturbances, including hypocholesterolemia and hype rtriglyceridemia, these results may provide an explanation for the alt ered pharmacokinetics and pharmacodynamics seen with L-Ann in these pa tients.