Pharmacokinetics and tissue distribution of etoposide delivered in long circulating parenteral emulsion

Abstract

Purpose: The aim of the study is to ascertain the influence of pegylation of parenteral emulsion (PE) on their long circulating property.

Methods: Etoposide encapsulated parenteral emulsion (EPE) was prepared using soybean oil, egg lecithin and cholesterol. Etoposide encapsulated long circulating parenteral emulsion (PEG–EPE) was prepared using PEG (2000)-DSPE as a stealth agent. The effect of monovalent and divalent electrolytes on the stability of EP was assessed by measuring the fixed aqueous layer thickness (FALT) and flocculation rate. Pharmacokinetics and tissue distribution pattern of PE following i.v. (bolus) were assessed in Wistar rats and Swiss albino mice.

Results: FALT of PEG–EPE was larger than that of EPE. In case of PEG–EPE, as the concentration of pegylated lipid (PEG) increased from 0.15 to 0.45% w/v the flocculation rate decreased asymptomatically in the presence of monovalent and divalent electrolytes. The increased circulation time of PEG–EPE (0.3%) after intravenous injection to rats confirms the presence of FALT around globules. PEG–EPE showed improved pharmacokinetic parameters with 5.5 times higher AUC than etoposide commercial formulation (ETP). Tissue distribution results show that etoposide levels in all tissues except in brain and heart were lower in case of PEG–EPE than ETP. The percentage of tumor growth suppression rate (%T/C) in Lewis lung carcinoma bearing mice was 63.23, 62.83 and 33.78% in EPE, PEG–EPE and ETP treated mice, respectively. The improved activity of PEG–EPE is due to enhanced permeability and retention effect (EPR).

Conclusion: Encapsulation of etoposide in PEG-coated PE produced improved pharmacokinetic profile than that of EPE and ETP.

Keywords: :

• Parenteral emulsion
• etoposide
• fixed aqueous layer thickness
• long circulating properties
• pharmacokinetics
• tissue distribution