Moreover, a lower multiple of the increase in BBR concentration after individual HIV PIs or Verapamil treatment in MDCK cells was observed in wild type MDCK cells, which may due to the lower levels of endogenous P-gp expression. The P-gp expression level in wild type MDCK cells is about 4% of that in P-gp-transfected MDCK cells. The molecular docking studies CCMQ further suggest that the inhibitory effect of individual HIV PIs on the P-gp transporter is as follows. These results also suggest that HIV PIs could competitively block the binding of BBR to its binding site in P-gp, while BBR has no reverse effect on the binding of HIV PIVs to their binding sites in P-gp. Taken together, our studies suggest that HIV PIs increase BBR concentrations mainly by inhibiting the activities of P-gp. It should be noted that it has recently been reported that HIV PIs are also inhibitors of breast cancer resistance protein and multidrug resistance-associated protein1. However, the expression of BCRP in murine macrophages has not been clearly identified and the role of MRPs and BCRP in the accumulation of BBR increased by HIV PIs remains to be established in our future study. It has been long realized that the bioavailability of BBR is very low in vivo. Several possible mechanisms have been identified for its poor bioavailability. P-gp-mediated efflux represents a major mechanism. Although inhibition of efflux of BBR by coadministration of HIV PIs may intuitively cause concern for use in clinic, this specific drug interaction may actually be beneficial to improve the biological activities of BBR. We will examine the effect of HIV PIs on bioavailability of BBR using an in vivo mouse model and further define the interaction between BBR and HIV PIs with other transporters in our future study. In summary, drug interactions of BBR with HIV PIs mediated by P-gp inhibition were suggested by in vitro studies using macrophages. Although further in vivo investigations of possible interactions are necessary, the current study provided valuable information for understanding the underlying cellular mechanism of BBR-HIV PIs interactions, which is critical to effectively applying this combinational therapy in the clinic. Tyrosine kinase inhibitors are nowadays frequently used for treatment of defined solid and hematological cancer entities. Although these drugs are typically developed for the targeting of single kinases which are specifically overexpressed in cancer cells, in reality they CNQX disodium salt usually inhibit a multitude of kinases and nonkinase targets resulting in a heterogeneous activity profile which is poorly predictable.