Comparison of the kinetics of active efflux of 99m Tc‐MIBI in cells with P‐glycoprotein‐mediated and multidrug‐resistance protein‐associated multidrug‐resistance phenotypes

The overexpression of two membrane glycoproteins, P‐glycoprotein and multidrug‐resistance protein (MRP 1 ) is a major cause of resistance to chemotherapeutic agents in the treatment of human cancers. Both proteins confer a similar multidrug‐resistant (MDR) phenotype. 99m Tc‐MIBI, a myocardial imaging agent, which is also useful for the detection of a variety of tumours, has been shown to be a substrate for P‐glycoprotein and MRP 1 . It thus may provide additional information about the P‐glycoprotein and MRP 1 status of tumour cells. In order to obtain information on the substrate specificity of these proteins, we have studied the transport kinetics of Tc‐MIBI in two cell lines, K562/ADR and GLC 4 /ADR, which overexpress P‐glycoprotein and MRP 1 , respectively. The mean active efflux coefficient k a , which is proportional to the ratio of maximal efflux rate V M to the apparent Michaelis‐Menten constant K m , used to characterise the efficiency of the active efflux, was very similar being 1.9 ± 0.6×10 −11 s −1 cells ml and 1.3 ± 0.5×10 −11 s −1 cells ml for drug‐resistant K562 and GLC4, respectively. These values are 50−100‐times lower than for daunorubicin and other anthracycline derivatives, strongly suggesting that the efficiency of both transporters to pump Tc‐MIBI is by far less than that to efflux anthracyclines. Our data show that (a) P‐glycoprotein and MRP transporter efficiencies to wash out Tc‐MIBI are similar, in spite of a different suspected mechanism of its transport and (b) that both transporters are less efficient to pump Tc‐MIBI than to pump anthracyclines (the k a parameter is about 100‐times lower for TC‐MIBI than for anthracycline).