Plasma pharmacokinetic and heart distribution studies of Z-GP-EPI, A hypocardiotoxic prodrug of Epirubicin

Abstract

Purpose: To explore the plasma pharmacokinetics and heart distribution of Z-GP-EPI, a low cardiotoxic prodrug of epirubicin (EPI). Methods: The drugs were administered to 20 rats (11. 22, 44 μmol/kg) by intravenous injection and 70 mice (30 μmol/kg) by tail intravenous injection. The profiles of Z-GP-EPI and EPI in rat plasma or mice heart were determined by high performance liquid chromatography (HPLC) method, which employed the Octadecylsilyl (ODS) column with a mobile phase of acetonitrile: 0.1% trifluoroacetic-water (42:58, v/v) at a flow rate of 1.0 mL/min and an ultraviolet (UV) detector at a wavelength of 495 nm. Pharmacokinetics parameters were calculated using a pharmacokinetic software. Results: Relative standard deviation (RSD) of intra- and inter-day precision values was < 15% in each case while method accuracy with recovery was between 85 and 110% for plasma and heart samples. After administration of 22 umol/kg Z-GP-EPI or EPI, terminal elimination half-life (t1/2) of Z-GP-EPI (1.41 h) was smaller than that of EPI (12.24 h). Furthermore, the concentration of Z-GP-EPI in heart rapidly decreased from 17.3 μg/g (0.05 h) to undetectable levels (2 h) while EPI changed from 14.3 μg/g (0.05 h) to 9.5 μg/g (2 h). Conclusion: The HPLC method established in this study is a feasible approach to detecting Z-GP-EPI and EPI in plasma and heart tissue. In addition, Z-GP-EPI is eliminated more rapidly from plasma and heart tissue than EPI, which probably contributes to the low cardiotoxicity of Z-GP-EPI.