Pharmacokinetics of epirubicin hydrochloride long-circulating thermosensitive liposomes in rat plasma

To develop and validate a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the quantification of epirubicin hydrochloride (EPI) in rat plasma, daunorubicin hydrochloride was used as internal standard.  The plasma samples were deproteinated with methanol, and separation was performed on a reversed-phase CAPCELL PAK C₁₈ column (3.0 mm × 50 mm, 3 μm).  The mobile phase contained methanol- 0.1% formic acid (80∶20).  Detection was carried out by multiple reaction monitoring on a HP1200-6410  QQQ LC/MS system.  Different preparations of EPI solution, EPI-LIP (EPI-liposome) and EPI-LTSL (EPI- thermosenstive liposome) was administered in rats by i.v with the same dosage (12 mg·kg⁻¹).  The pharmacokinetic model and parameters were fitted and calculated by the DAS ver2.0 software.  The calibration curve was linear in the range of 0.01−50 μg·mL⁻¹.  The limit of quantification was 0.01 μg·mL⁻¹.  RSDs of intra- and inter- batch precisions were all less than 11.9%.  The average extract recovery was 89.3% and 92.1%, respectively.  The pharmacokinetics of EPI in rats with all preparations were fitted to three compartments, which all fast   distributed and slowly eliminated.  The t_1/2α, t_1/2β, t_1/2γ, AUC_0−∞, and MRT_0−∞ of EPI-LTSL group were 7.5, 1.3, 12.6, 12.9, 3.7 times those of EPI solution group; and 1.6, 1.4, 12.3, 2.9, 2.6 times those of EPI-LIP group.  Moreover, the CL of the latter two groups was about 13.4 times of the former EPI-LTSL group.  EPI-LTSL can significantly improve AUC and prolong the circulation time of EPI in rat plasma.