Distribution of free and liposomal annamycin within human plasma is regulated by plasma triglyceride concentrations but not by lipid transfer protein

K. M. Wasan, Roman Perez-Soler

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

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 multilamellar 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) traction 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.

Original languageEnglish (US)
Pages (from-to)1094-1100
Number of pages7
JournalJournal of Pharmaceutical Sciences
Volume84
Issue number9
DOIs
StatePublished - 1995
Externally publishedYes

Fingerprint

Plasma (human)
Triglycerides
Plasmas
VLDL Lipoproteins
Pharmacokinetics
Pharmacodynamics
Lipoproteins
Dimyristoylphosphatidylcholine
lipid transfer protein
annamycin
Liposomes
Lipids

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Chemistry(all)
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science

Cite this

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title = "Distribution of free and liposomal annamycin within human plasma is regulated by plasma triglyceride concentrations but not by lipid transfer protein",
abstract = "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 multilamellar 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) traction 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.",
author = "Wasan, {K. M.} and Roman Perez-Soler",
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T1 - Distribution of free and liposomal annamycin within human plasma is regulated by plasma triglyceride concentrations but not by lipid transfer protein

AU - Wasan, K. M.

AU - Perez-Soler, Roman

PY - 1995

Y1 - 1995

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 multilamellar 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) traction 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 multilamellar 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) traction 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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