摘要
目的：评价埃克替尼在大鼠和比格犬体内的药动学和在大鼠体内的组织分布。方法：大鼠和比格犬单次iv或ig/po给予盐酸埃克替尼混悬剂或溶液,评价其药动学特性,大鼠ig给药后测定埃克替尼在大鼠各组织的分布,采用体外透析法测定血浆蛋白结合率。结果：大鼠和比格犬iv给药,埃克替尼的血浆消除半衰期分别为3.23和5.6 h,清除率分别为8.95和9.57 mL·min-1·kg-1。混悬液ig/po给药,大鼠和比格犬的绝对生物利用度（F）分别为51.3%和27.4%,溶液剂给药时比格犬的F值为62.8%。埃克替尼在雌性大鼠的AUC约为雄性的3~5倍,而比格犬药动学无性别差异。埃克替尼可快速且广泛分布于大鼠组织,给药后4 h内,胃肠道和肝脏中浓度高于血浆浓度。埃克替尼在人和大鼠的血浆蛋白结合率均大于98%。结论：埃克替尼在动物体内具有较好的药动学特性,支持该药物的进一步开发。
Objective; To evaluate the pharmacokinetics of icotinib and its tissue distribution in preclinical species.Methods：The pharmacokinetic profiles were characterized in single oral and intravenous doses to rats and dogs as suspension and solution formulations.Tissue distribution was assessed following a single oral dose in rats and the extent of protein binding was determined in rat and human plasma.Biological samples from the in vivo and in vitro studies were analyzed using HPLC-UV and LC/MS/MS methods for the quantification of icotinib.Results：Icotinib declined both in rat and dog systemic circulation,with a terminal t1/2of 3.23 and 5.6 h and a relatively low clearance of 8.95 and 9.57 mL·min-1·kg-1,respectively.It showed an approximately linear pharmacokinetic profile over the tested dosage range following oral administration.The absolute oral bioavailability of icotinib given as suspension was 51.3% in rats and 27.4% in dogs,respectively,and that given as solution was 62.8% in dogs.The exposure of icotinib was 3 to 5-fold higher in female than in male rats,but no sex difference was found in dogs.Icotinib exhibited high plasma protein binding（＆gt; 98%） which was concentration and species independent.Tissue distribution studies in rats showed that icotinib distributed to tissues rapidly and extensively.Stomach,intestine and liver showed higher exposure than plasma within 4 h post dose.Conclusion：Icotinib exhibits good pharmacokinetic profile in preclinical species,which supports its development in human.
出处
《中国新药杂志》
CAS
CSCD
北大核心
2014年第2期235-240,共6页
Chinese Journal of New Drugs
