Metabolic Study Of Lung-targeted DTX-LP In Different Animals

BackgroundAs one of the most serious malignant tumors to health and life,the morbidity and mortality of lung cancer are increasing.About 80% of lung cancers are non-small cell lung cancer(NSCLC).The clinical treatment of NSCLC's docetaxel injection(DTX-IN)lacks lung targeting,large doses,and the solubilizing agent Tween 80 in the injection may cause allergic and other side effects.Therefore,an ideal therapeutic strategy is to develop a formulation with lung targeting.Our group selected liposome technology,using DTX as a model drug,using a new docetaxel liposome(DTX-LP)developed by solid dispersion technology and hydration technology,which was proved in rabbits by experiments.With significant lung targeting,it can improve the treatment of lung cancer and reduce systemic side effects.ObjectiveIn this paper,rabbits,rats and mice were used as research objects to study the similarities and differences of metabolism and excretion of new lung-targeted DTX-LP independently developed by our group in rabbits,rats and mice.MethodsDetection of four known metabolites of DTX and M1/3,M2 and M4 in bile and feces samples collected from rabbit,rat and mouse in different time periods after administration by UPLC-MS/MS method.Results1.Metabolic experiments in rabbits,rats and mice showed that DTX and M1/3,M2 and M4 were present in the feces samples of DTX-LP group and DTX-IN group,and DTX and M1/3 and M2 were present in bile samples.The metabolite M4 is only present in the feces and not in the bile sample,it is speculated that the metabolite M4 may only form in the intestinal contents or in the feces.The metabolic pathways and metabolites of DTX-LP and DTX-IN were basically the same,and it was concluded that DTX-LP did not have the safety problem of metabolites.2.Compared with the DTX-IN group,DTX has a delayed metabolism in the DTX-LP group,suggesting a delay in the metabolic conversion of DTX-LP in vivo.3.In addition,in rabbit and rat feces,the two preparations were mainly excreted by the prototype drug DTX,and the dominant metabolite was M2.In the mouse feces,the two preparations were mainly excreted by the metabolite M2,followed by the metabolite M1/3,then the metabolite M4,and finally DTX.This indicates that the in vivo metabolism of DTX has certain species differences.4.An unreported metabolite with an m/z of 839 was found in rabbit and rat feces.ConclusionIn summary,DTX-IN was used as a control to study the drug metabolism of DTX-LP in rabbits,rats and mice.The results of in vivo metabolism experiments showed that the DTX-LP prepared by our group was basically consistent with the metabolic pathways and product types of the injection dosage form.The liposome only delayed the time of metabolic conversion of DTX in vivo,which is the clinical application of DTX-LP.Security provides evidence.However,the metabolism of DTX in differentanimals has certain differences,which provides a reference for the selection of DTX-LP in preclinical experimental animal models.