Effects of clinical P-glycoprotein inhibitors on oral bioavailability and brain penetration of gefitinib
10.11665/j.issn.1000-5048.20190212
- VernacularTitle: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
- Author:
Yanqing WU
1
;
Qingqing CAO
;
Ting ZHANG
;
Yu ZHAI
;
Wenping LI
;
Jin YANG
Author Information
1. 中国药科大学药物代谢与动力学研究中心
- Publication Type:Journal Article
- Keywords:
gefitinib;
brain penetration;
P-glycoprotein;
co-administration;
pharmacokinetics
- From:
Journal of China Pharmaceutical University
2019;50(2):206-212
- CountryChina
- Language:Chinese
-
Abstract:
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 IC50 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.
