外排转运蛋白P-糖蛋白、乳腺癌耐药蛋白对氟康唑脑内分布的影响  

Effect of efflux transporter P-gp or breast cancer-resistance protein on the distribution of fluconazole in rat brain

作　　者：王威[1] 郑娜[1] 邵龙[1] 蒋胶胶 张家堂[1] WANG Wei ZHENG Na SHAO Long JIANG Jiaojiao ZHANG Jiatang(Department of Neurology, Chinese PLA General Hospital, Beijing 100853, China)

机构地区：[1]解放军总医院神经内科,北京100853

出　　处：《解放军医学院学报》2017年第7期671-674,共4页Academic Journal of Chinese PLA Medical School

摘　　要：目的探索表达于血-脑屏障上的外排转运蛋白P-糖蛋白(P-glycoprotein,P-gp)和乳腺癌耐药蛋白(breast cancerresistance protein,BCRP)对氟康唑脑内分布的影响。方法 18只SD大鼠随机分为A组(n=6):股静脉注射氟康唑20 mg/kg,为对照组;B组(n=6):注射氟康唑前30 min股静脉注射P-gp抑制剂维拉帕米5 mg/kg;C组(n=6):注射氟康唑前30 min股静脉注射BCRP抑制剂泮托拉唑40 mg/kg。建立大鼠脑微透析模型,静脉给予氟康唑后连续采集脑细胞外液,并同步采集血液,利用高效液相色谱技术检测样本中氟康唑浓度并计算氟康唑的血-脑屏障透过率。通过比较加用抑制剂组与对照组氟康唑血-脑屏障透过率的差异来判断两种外排转运蛋白对氟康唑脑内分布的影响。结果 A组大鼠血-脑屏障透过率为62.7%±12.4%,B组大鼠血-脑屏障透过率为81.4%±15.5%,B组显著高于A组(P<0.05);C组大鼠血-脑屏障透过率为63.0%±12.1%,与A组无统计学差异(P>0.05)。结论外排转运蛋白P-gp参与了血-脑屏障对氟康唑的抵抗,其抑制剂可显著提高氟康唑的血-脑屏障透过率;BCRP未参与血-脑屏障对氟康唑的抵抗,加用其抑制剂不能改变氟康唑的血-脑屏障透过率。Objective To explore the effect of P-glycoprotein （P-gp） or breast cancer-resistance protein （BCRP） on the distribution of fluconazole in rat brain. Methods Sprague–Dawley rats （n=18） were divided into 3 groups randomly with group A （n=6） receiving an intravenous injection of 20 mg/kg fluconazole, rats in group B （n=6） receiving 20 mg/kg fluconazole and 5 mg/kg P-gp inhibitor verapamil, rats in group C （n=6） receiving 20 mg/kg fluconazole and 40 mg/kg BCRP inhibitor pantoprazole, respectively. Microdialysis probes were implanted into the SD rats’ striatums to collect their brain extracellular fluid （ECF） continuously after the intravenous injection of fluconazole, and the fluconazole concentrations in the blood and brain ECF were measured using highperformance liquid chromatography （HPLC） technique . Then, the penetration rate of fluconazole into the blood-brain barrier （BBB） was compared between treatment groups （Group B or C） and control group （Group A） to estimate the effect of P-gp and BCRP on the distribution of fluconazole. Results Penetration rate in group B was 81.4%±15.5%, significantly higher than 62.7%±12.4% in group A and 63.0%±12.1% in group C （P ＜ 0.05, respectively） with no significant difference in the latter two groups. Conclusion P-gp at the BBB impedes the influx of fluconazole into the brain, and its inhibitor can increase the penetration rate of fluconazole into BBB, while the BCRP does not involved in transporting fluconazole between blood and brain.

关 键 词：血- 脑屏障 P- 糖蛋白 乳腺癌耐药蛋白 氟康唑 微透析 

分 类 号：R978.5[医药卫生—药品]