Figure 2.

Hypothesized mechanism of the enhanced efficacy of drug pretreatment before verapamil administration and PGP blockade. A. HCC cells expressing active PGP can expel a drug (e.g., sunitinib) from the cytoplasm or store it in lysosomes. B. Blocking PGP with verapamil before the coadministration of sunitinib and verapamil allows the drugs to enter the cell and diffuse into cytoplasm/nucleus. C. If sunitinib is used for pretreatment, it is stored in giant lysosomes, and after the coadministration of sunitinib and verapamil and subsequent PGP blockade, the drugs can enter the cytoplasm/nucleus from both extracellular space and the lysosomes (19).