| Docetaxel, one of the most important anti-cancer drugs now ,is a semi-synthesized taxane compounds.It is effective to cure recurrent ovarian cancer,breast cancer and non-small cell lung cancer. However doctacxel has clinic ADR including nausea,vomit,hemafecia,arthralgia,courbature and neutropenia caused by myelosuppression,meanwhile with the low solvability in water,doctacxel is formulated using Tween 80(polysorbate 80)and 13% ethanol.Acute hypersensitivity reactions and allergies have been noted in the majority of patients,which partially come from using of Tween 80.All mentioned above restricted the clinic use of doctacxel .there is increasing number of novel preparations were reported including liposome ,Nano-emulsion, Microemulsion. Docetaxel Injection is a novel preparation of anti-tumor drugs Docetaxel which is freeze-dry powder injector(an excipient including gallate-hydroxypropyl-β-cyclodextrin ,Glycine, Mannitol),improved its Solubility ,in order to relive the ADR caused by tween 80.This article aims to develop a method of LC-MS/MS to determine the concentration of. Docetaxel Injection in bio-samples. Agilent Eclipese XDB-C18(4.6mm×200mm,1.8μm)was choosen to be the chromatographic column and the detection temperatue at 30℃, taking methanol(0.1% methanoic acid)- water(5% acetonitrile, 0.1% methanoic acid) (75:25 V/V) as mobile phase with the flow rates of 0.4mL/min, and the injection volume is 5μL and paclitaxel was selected to be the internal standerd gipizide. Parent iron m/z 830.3 and m/z 876.3 were used for quantification of docetaxel and internal standard glipizide, respectively .The plasma sample was extracted twice by aether.. The mothod is sensitive, fast and simple. Docetaxel concentration was linear over the range of 2-500μg·L-1; the limit qulification was 2μg·L-1. The inter-day and the intra-day precision (RSD) ranged from 2.4% to 10.9% and 3.9% to 7.0% respectively. Extraction recovery was above 89.2% for the concentration of 5, 50, 500μg·l-1 of samples respectively. Blood sample were stable for 24 hours in 25℃and 4℃。Extraction samples were stable for 3 monthes. Docetaxel injection was been intravenous injected in 4 weeks repeat administration toxicity test with toxicokinetic test in beagle dogs .contraction the original preparation and novel preparation with confirmed and detectable method of LC-MS/MS and analysed parametrics including Cmax, AUC and MRT in the same dose groups of novel preparation and original preparation in first and last time administration .results show that docetxel concentration in beagle dogs plasma descended as characters of two exponential function .the elimination is fast in 0-30 min after intravenous drip while afer 30 minites elimation rate showsdown . trace amount of docetxel could be determined 8 hours after intravenous drip. Cmax ratio was 1:3.4:2.9 (low: :midium: high dose ) and AUC ratio was 1:2.8:3.4 (low: midium: high dose ) in three dose groups in the first administration which shown that docetexl explosure in plasma was dose-dependent,while Cmax ratio was 1:1.4:1.4 (low: midium: high dose) and AUC ratio was 1:1.5:1.3 (low: midium: high dose ) in three dose groups in the last administration which also shown dose-dependent.Compared with the first administration after the last time of intravenous drip AUC and Cmax in low dose group were significant increased however kinetic parameters in medium and high dose group had no significant differences. From the above, kinetic parameters haven't been changed after three times of iintravenous drip. No matter the first or the last administration ,AUC of control drug of docetxel was twice of docetexle injection which means the original preparation Systemic explosure is higher than the novel one.Two treatment, and two period random cross-over experiment were given to beagle dogs in order to observe the differences between the two drugs in the same doses(1.0 mg·kg-1or 2.5 mg·kg-1).The result shown that no matter dose group of 1.0 mg·kg-1 or 2.5 mg·kg-1, Cmax and AUC of docetxel injection is significantly lower than control drug while Vd of were significantly higher than control drug which indicated that novel preparation of injection was lower than original one.To observe the tissue distribution differences between docetxel injection and control drug in distribution study in 6 SD rats which were randomized into two grops and treated intravenously with 12 mg·kg-1 of docetexl injection and control drug respectively. The result indicated that concentration of docetexl injection has been detective much higher than control drug in most of tissure in 5 min after tail intravnouse injection,especially in fat,heart,spleen lung, gastrointestinal tract. Concentration of docetexl injection still higher than control drug in most tissure which were detectived expect spleen in 1hour after administration. Concetration of docetexl turned to identical in 4 hours after administration most of tissue detectived except lung which detectived more docetexle in novel preparation than in original one .Compare with control drug of docetexl injection,exposure of novel preparation of docetexl injection in plasma is lower but higher in tissue. |
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