TY - JOUR
T1 - Distribution of free and liposomal annamycin within human plasma is regulated by plasma triglyceride concentrations but not by lipid transfer protein
AU - Wasan, Kishor M.
AU - Perez‐Soler, Roman
N1 - Funding Information:
Work was partially supported by a grant (to K.M.W.) from Argus Pharmaceuticals. We want to thank Dr. Richard E. Morton for his guidance and expertise on this project. K.M.W. is a fellow of the American Society of Pharmacology and Experimental Therapeutics.
PY - 1995/9
Y1 - 1995/9
N2 - Annamycin (Ann) is a lipophilic and non‐cross‐resistant anthracycline antibiotic currently in clinical development as a liposomal formulation (L‐Ann) composed of dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylglycerol (DMPG). Previous studies have demonstrated that the incorporation of Ann into these liposomes prolongs its terminal 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 multi‐lamellar lipid vesicles remains unknown. Since the distribution of lipophilic compounds within plasma lipoproteins has been shown to influence the pharmacokinetics 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 lipoproteins and the influence of LTP on the distribution of Ann and L‐Ann among plasma lipoproteins. Our results concluded that when Ann was incorporated into liposomes composed of DMPC and DMPG, over 65% of the initial Ann concentration would distribute into the high density lipoprotein (HDL) fraction and that free Ann and L‐Ann distribution within human plasma was independent of LTP activity. In addition, we observed that the increase in total plasma triglyceride (TG) concentrations (through the increase of very low‐density lipoproteins (VLDL)) resulted in the increase distribution of Ann and L‐Ann within the TG‐rich VLDL fraction. However, increasing the VLDL core TG/cholesterol ratio decreased Ann distribution into VLDL. These findings suggest that initial Ann distribution is regulated by a mechanism that does not involve LTP, but through its interaction with plasma VLDL—TG. Since many cancer patients exhibit lipid disturbances, including hypocholesterolemia and hypertriglyceridemia, these results may provide an explanation for the altered pharmacokinetics and pharmacodynamics seen with L‐Ann in these patients.
AB - Annamycin (Ann) is a lipophilic and non‐cross‐resistant anthracycline antibiotic currently in clinical development as a liposomal formulation (L‐Ann) composed of dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylglycerol (DMPG). Previous studies have demonstrated that the incorporation of Ann into these liposomes prolongs its terminal 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 multi‐lamellar lipid vesicles remains unknown. Since the distribution of lipophilic compounds within plasma lipoproteins has been shown to influence the pharmacokinetics 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 lipoproteins and the influence of LTP on the distribution of Ann and L‐Ann among plasma lipoproteins. Our results concluded that when Ann was incorporated into liposomes composed of DMPC and DMPG, over 65% of the initial Ann concentration would distribute into the high density lipoprotein (HDL) fraction and that free Ann and L‐Ann distribution within human plasma was independent of LTP activity. In addition, we observed that the increase in total plasma triglyceride (TG) concentrations (through the increase of very low‐density lipoproteins (VLDL)) resulted in the increase distribution of Ann and L‐Ann within the TG‐rich VLDL fraction. However, increasing the VLDL core TG/cholesterol ratio decreased Ann distribution into VLDL. These findings suggest that initial Ann distribution is regulated by a mechanism that does not involve LTP, but through its interaction with plasma VLDL—TG. Since many cancer patients exhibit lipid disturbances, including hypocholesterolemia and hypertriglyceridemia, these results may provide an explanation for the altered pharmacokinetics and pharmacodynamics seen with L‐Ann in these patients.
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U2 - 10.1002/jps.2600840912
DO - 10.1002/jps.2600840912
M3 - Article
C2 - 8537888
AN - SCOPUS:0029122889
SN - 0022-3549
VL - 84
SP - 1094
EP - 1100
JO - Journal of Pharmaceutical Sciences
JF - Journal of Pharmaceutical Sciences
IS - 9
ER -