Epithelial Transfer of the Tyrosine Kinase Inhibitors Erlotinib Gefitinib Afatinib Crizotinib Sorafenib Sunitinib and Dasatinib: Implications for Clinical Resistance

摘要

Tyrosine kinase inhibitors (TKIs) specifically inhibit phosphorylation of signaling pathways of cancer cells, thereby inhibiting their growth. They are characterized by a poor solubility and high protein binding, leading to a large variability in gut uptake after oral administration and variation in the clinical efficacy. We used the CaCo2 gut epithelial model to characterize the gut absorption of 7 TKIs and observed a large variation in apical/basolateral (mimicking gut/blood) transfer, with 4 TKIs showing a negative and 3 a neutral transfer. A highly negative transfer may lead to pharmacokinetic resistance. Intracellular uptake of TKIs was high for sunitinib and crizotinib, intermediate for gefitinib, dasatinib and sorafenib, low for afatinib and not detectable for erlotinib. These properties may explain a high red blood cell to plasma ratio for most TKIs investigated. Although TKIs are poorly absorbed the latter property may compensate for this.