P-gp is involved in the intestinal absorption and biliary excretion of afatinib in vitro and in rats

Pharmacological Reports - Tập 70 - Trang 243-250 - 2017
Yan Zhang1,2, Changyuan Wang1,3, Zhihao Liu1,3, Qiang Meng1,3, Xiaokui Huo1,3, Qi Liu1,3, Pengyuan Sun1,3, Xiaobo Yang1,3, Huijun Sun1,3, Xiaodong Ma1,3, Kexin Liu1,3
1Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China
2Peking University Third Hospital Yanqing Hospital, Beijing, China
3Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University, Dalian, China

Tóm tắt

Afatinib is an irreversible multi-targeted TKI, used in the treatment with EGFR mutated non-small cell lung cancer (NSCLC). The purpose of this study is to explore the molecular pharmacokinetic mechanism underlying the effect of P-gp inhibitors on the intestinal absorption and biliary excretion and to understand how P-gp inhibitors affect afatinib pharmacokinetics. Pharmacokinetics in vivo, in situ intestinal perfusion, perfused rat liver in situ, Caco-2 cells, P-gp ATPase activity, sandwich-cultured rat hepatocytes (SCRH) and transfected-cell transport were used in the evaluation. P-gp inhibitor verapamil (Ver) markedly increased the plasma concentrations and significantly decreased the biliary excretion of afatinib in vivo. Ver increased the intestinal absorption and decreased biliary excretion of afatinib in situ single-pass intestinal perfusion studies and in situ perfused rat liver, respectively. The accumulation of afatinib in Caco-2 cells was enhanced by Ver and Cyclosporin A (CsA). The biliary excretion index (BEI) of afatinib in SCRH was decreased by Ver and CsA, respectively. The net efflux ratio of afatinib was 2.3 across vector-/MDR1–MDCKII cell monolayers and was decreased by P-gp inhibitor. The activity of P-gp ATPase was induced by afatinib and the Km and Vmax were 1.05 μM and 59.88 nmol ATP/mg hP-gp/min, respectively. At least partly P-gp is involved in increasing the intestinal absorption and decreasing the biliary excretion of afatinib in rats.

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