99mTc-sestamibi is a substrate for P-glycoprotein and the multidrug resistance-associated protein

Tc-99m-sestamibi (Tc-99m-MIBI) is a substrate for the P-glycoprotein (P-gp) pump but it is not known whether it is a substrate for the multidrug resistance-associated protein (MRP) pump. Therefore, Tc-99m-MIBI was evaluated in the GLC(4) cell line and its doxorubicin-resistant MRP-, but not P-gp-, overexpressing GLC(4)/ADR sublines as well as in the S1 cell line and its MRP-transfected subline S1-MRP. Tc-99m-MIBI concentration decreased in the GLC(4)/ADR sublines with increasing MRP overexpression and was lower in S1-MRP than in S1. Tc-99m-MIBI plus vincristine increased Tc-99m-MIBI concentration in GLC(4) lines compared with Tc-99m-MIBI alone. Tc-99m-MIBI efflux raised with increasing MRP expression in the GLC(4) lines. Glutathione depletion elevated Tc-99m-MIBI concentration in GLC(4)/ADR(150x). Cross resistance for Tc-99-MIBI, used to test cytotoxicity of the Tc compound, was observed in GLC(4)/ADR(150x) vs GLC(4). Tc-99-MIBI induced a synergistic effect on vincristine cytotoxicity in GLC(4)/ADR(150x). These results show that Tc-99m-MIBI is involved in MRP-mediated efflux. The fact that Tc-99m-MIBI efflux is influenced by MDR1 and MRP expression must be taken into account when this gamma-rays-emitting complex is tested for tumour efflux measurements.