Pharmacokinetics And Tissue Distribution Of Docetaxel Liposome Mediated By Novel Galactosylated Cholesterol Derivatives

Objective5-cholesten-3 β-yl [(4-0-β-D-galactopyranosyl) D-glucitol-6] decanedioic acid (CHS-DD-LA) is a new galactose ligand prepared by lipases in nonaqueous phase, which can be identified by ASGP-r on the parenchymal hepatic cells and can be used as "head" of hepatic targeted drug delivery system such as liposome, polymeric micelles and other particle delivery systems. Docetaxel liposomes has been successfully prepared by our team, based on its preparation technology, liposomes mediated by this galactose ligand was prepared. Quality standards investigation has showed that it is in line with Chinese Pharmacopoeia. The purpose of this article was to investigate the pharmacokinetic characters and liver targeting of mediated liposomes, and to establish LC-MS/MS measure for docetaxel in plasma and tissue samples, thus in order to lay root for new drug approval of this mediated liposomes and the further non-clinical study.Methods1. LC-MS/MS determination was selected for the content of docetaxel in plasma and tissue samples. Taxol was used as internal standard.2. SD rats were slected as model animal. Firstly, the pharmacokinetic of mediated liposomes in different doses:2.5mg-kg-1、5mg-kg-1、7.5mg-kg-1 were investigated. The observation time were:0.083h、0.25h、0.5h、1h、2h、4h、 6h、8h、10h、24h. Then one apposite dose was selected in order to set up three different groups:conventional liposomes of docetaxel and docetaxel injection. Comparing their pharmacokinetic parameters and drawing C-T curve by DAS 2.0.3. KM mice were selected as model animal to investigated the distribution of mediated liposomes for different time:5mi、10mi、20min、30min、60min、 120min、240min.4 parameters:Relative intake rate (Re), Targeting efficiency (Te), Relative targeting efficiency (RTe), Peak concentration ratio (Ce) were indued to characterize the liver targeting compared with other groups of conventional docetaxel liposomes and docetaxel injection.Results1. This paper has established LC-MS/MS detection method for the docetaxel concentration in plasma and tissue samples. Using taxel as internal standard, the study of specificity, linearity, accuracy, precision indicates that it is a excellent detection method. And a good extraction recovery indicates that the processing method of plasma and tissue samples used in this paper is feasible.2. After a single tail vein injection of mediated liposomes for rat at the dose of 2.Smg·kg-1、5mg·kg-1,7.5mg·kg-1, the Cmax, AUC has showed a dose related, while t1/2, CL has no dose relevance. Other pharmacokinetic parameters has no significant difference. Low dose was used as the reasonable dose for three different groups. Different groups of rats get injected by mediated liposomes, conventional docetaxel liposome, and docetaxel injection. The pharmacokinetic parameters distribution half-life t1/2 (h) respectively are 0.13±0.027,0.06±0.012,0.02±0.007; Clearance CL are 1.71±0.164,2.31 ±0.118,4.08±0.803, and the average residence time MRT are 2.46±0.089, 2.10±0.121,1.67±0.212。3. After a single tail vein injection of conventional liposomes and mediated liposomes for mice, the targeting parameters Re respectively are 1.642±0.124,5.478±0.621; RTe are 1.843±0.086,4.823±0.291; Ce are 1.792 ±0.097、3.888±0.140, Te(%) of mediated liposome, conventional docetaxel liposome, and docetaxel injection are 59.560±3.011 22.754±0.804,12.349 ±0.338. Conelusions1. This study has established the LC-MS/MS detection of docetaxel concentration in plasma and tissue samples, the method has many advantages of convenient, sensitive, specific and reproducible. It offers a available detection method in further animal and clinical pharmacokinetic study.3. The pharmacokinetic parameters in rats with different doses were according to the basic two compartment model, pharmacokinetic parameters AUC and Cmax was significantly dose-related; by analysis of variance, low, medium, and high dose groups t1/2 has no significance, showing that there exist no non-linear pharmacokinetic profile. Compared with conventional liposomes and docetaxel injection, the t1/2。, MRT, V1 has decreased and CL has increased, demonstrating that the mediated liposomes in rats can quickly distribute in organs and be cleared faster. Speculating that it may relate to its high liver uptake.4. After single intravenous administration of mediated liposome.The mice tissues distribution of docetaxel concentration are:liver>lung>kidney> pleen>heart. Compared with conventional liposomal, mediated liposomes significantly improve the targeting effect in liver, demonstrating that with the modification of galactose ligand, not only has improved the liver targeting but also decrease the toxicity of docetaxel liposomes.