Pharmacokinetics Studies Of Vinorelbine Nanomicelles

Vinorelbine is a vinca-alkaloid obtained by chemical semi synthesis. Vinorelbine inhibits microtubule assembly, and thus its activity is cell cycle specific. Clinically, vinorelbine is a potent anti-cancer drug widely prescribed for advanced non-small-cell lung cancer and advanced breast cancer.Like most of conventional chemotherapeutic agents, vinorelbine is distributed nonspecifically in the body where it affect both cancerous and normal cells, thereby resulting in excessive toxicities and limiting the dose achievable within the tumor. Nanomicelle, by using both passive and active targeting strategies, thus enhancing the efficacy and reducing the toxicity of antitumor agents.The thesis aimed to study the preclinical pharmacokinetics of vinorelbine nanomicelle (M-VRL) and free vinorelbine (F-VRL) in rats and mices by LC-ESI/MS and LC-ESI/MS/MS, to exactly predict the transformation of vinorelbine in human, to rationally evaluate the efficiency and security of vinorelbine, and to offer some references and inspirations for the clinical studies.This study is an important part of National 973 Plan Foundation of China (No. 2006CB933303). Results with both scientific and practical significance were listed as follows:1. The cytotoxicities and pharmacodynatics research of M-VRL and F-VRL To analyze the pharmacodynatics of M-VRL and F-VRL, the mouse models using 4T1 cells were established by injecting tumor cell suspension, and the cytotoxicities of M-VRL and F-VRL were examined by MTT method. The result showed that the M-VRL have high cytotoxicities for 4T1 cells and high effect of tumor growth inhibition.2. The development of LC-ESI/MS method for the determination of vinorelbine in plasma samplesThe optimized chromatography and mass condition for the determination of vinorelbine in rat plasma were obtained after a serial of experiments, and then a rapid, highly sensitive, accurate high performance liquid chromatography-mass spectrometric (LC-ESI/MS) method was developed and fully validated. Compared to the reported method, the evaluation results of hundreds of plasma samples proved that this novel method performed better in sensitivity, specificity as well as time-saving,and was enough to qualify its application in the pharmacokinetics study.3. Studies on pharmacokinetics of vinorelbine in rats.A rapid and sensitive LC-ESI/MS method has been successfully applied to a pharmacokinetic study in rats after a single iv administration of M-VRL and F-VRL. The result showed that the M-VRL and F-VRL in rats were best fitted to two-compartment model.4. Excretion studies of vinorelbine in rats.In the present study, we also did some vinorelbine study for both M-VRL and F-VRL. LC-ESI/MS was developed for urine and feces sample determination and analysis to research time-related changes of vinorelbine in rat urine and feces to M-VRL and F-VRL. Combined with the results of studies, the information was further provided for researching mechanism of excretion.5. Tissue distribution study of vinorelbine both in rats and mice.A sensitive and selective high performance liquid chromatography-tandem mass spectrometric (LC-ESI/MS/MS) method for the quantification of vinorelbine in rats and mice tissues was validated and successful applied for the tissue distribution study of M-VRL and F-VRL both in rats and mices.Through comparison the difference between tissue distribution of M-VRL and F-VRL, the targeting effect and accumulate situation of vinorelbine in the internal tissues both in rats and mice were evaluated.In conclusion, the LC-ESI/MS and LC-ESI/MS/MS methods were developed and applied to systemically evaluate the pharmacokinetics, distribution and excretion of vinorelbine after an i.v. injection. The distribution profile of vinorelbine in tumor and normal tissues were investigated. Reliable scientific basis was provided for the clinical development of vinorelbine.In this thesis, the novel LC-ESI/MS and LC-ESI/MS/MS method characterized by high-throughput, high sensitivity and specificity were developed for the determination of vinorelbine. These methods were of great reference value for in vivo analysis of vinorelbine.