16种具有P-gp抑制作用的上市药物对吉非替尼口服生物利用度和脑通透性的影响  

Effects of clinical P-glycoprotein inhibitors on oral bioavailability and brain penetration of gefitinib

作　　者：吴延庆 曹青青 张婷 翟宇 李文萍 杨劲[1] WU Yanqing;CAO Qingqing;ZHANG Ting;ZHAI Yu;LI Wenping;YANG Jin(Center of Drug Metabolism and Pharmacokinetics,China Pharmaceutical University Nanjing 210009,China)

机构地区：[1]中国药科大学药物代谢与动力学研究中心,南京210009

出　　处：《中国药科大学学报》2019年第2期206-212,共7页Journal of China Pharmaceutical University

基　　金：中国药科大学双一流学科创新团队项目资助(No.CPU2018GY24)~~

摘　　要：采用LC-MS/MS法研究16种具有P-gp抑制作用的上市药物对吉非替尼口服生物利用度和脑通透性的影响。对照组ICR小鼠灌胃给予CMC-Na混悬液和吉非替尼混悬液,抑制剂组ICR小鼠分别灌胃给予16种上市药物混悬液和吉非替尼混悬液,血浆样品和脑匀浆样品经乙腈沉淀后,用LC-MS/MS法测定药物浓度。结果发现16种药物中利托那韦能够明显增加吉非替尼的口服生物利用度,吉非替尼血药浓度-时间曲线下面积(AUC)增加了2倍,同时增加了吉非替尼的脑暴露量,但是没有增加吉非替尼的脑通透性;部分其他药物也能增加吉非替尼的血浆AUC,不能增加吉非替尼的脑通透性;游离分数校正脑浓度发现对照组和给予利托那韦后,脑内游离药物浓度均不能达到体外抑制非小细胞肺癌(NSCLC)细胞生长的IC_(50)。本研究结果表明,临床剂量的16种具有P-gp抑制作用的上市药物虽然能够增加吉非替尼的口服生物利用度,但是不能特异性提高脑组织暴露量,需要研发特异性更强和更安全的P-gp抑制剂;用脑部药物游离分数校正脑浓度后,临床前研究发现脑暴露量不足可能是吉非替尼治疗脑转移疗效不理想的原因之一。To investigate the effects of clinical P-glycoprotein inhibitors on oral bioavailability and brain penetration of gefitinib,16 inhibitors and gefitinib were co-administered orally to ICR mice.The suspension of gefitinib and CMC-Na were co-administered to the control group.The suspension of gefitinib and clinical P-glycoprotein inhibitors were co-administered to the control group.Blood samples and brain homogenate samples were extracted by protein precipitation with acetonitrile and determinated by LC-MS/MS.It was found that ritonavir can significantly increase the oral bioavailability of gefitinib,and the area under the plasma concentration-time curves (AUC) of gefitinib was increased by 2 times;while brain exposure was increased,there was no increment in brain penetration.Some other drugs can also increase the plasma AUC of gefitinib,but can not enhance the brain penetration;After we corrected brain concentration with fraction of unbound drug in brain,it was found that the brain concentration of gefitinib in both control group and ritonavir group did not achieve the in vitro IC 50 of inhibiting non-small cell lung cancer (NSCLC) cell growth.Our results suggest that clinical doses of the 16 clinical P-glycoprotein inhibitors can not specifically increase brain tissue exposure,more specific and safer P-gp inhibitors are required.After we corrected brain concentrations with fraction of unbound drug in brain,our preclinical studies found that insufficient brain exposure may be one of the reasons for the unsatisfactory efficacy of gefitinib in the treatment of brain metastases.

关 键 词：吉非替尼 脑通透性 P糖蛋白 联合用药 药代动力学 

分 类 号：R969[医药卫生—药理学]