Visualization of multidrug resistance in vivo

Various mechanisms are involved in multidrug resistance (MDR) for chemother apeutic drugs, such as the drug efflux pumps, P-glycoprotein (Pgp) and mult idrug resistance-associated protein (MRP). In this review the mechanisms in volved in MDR are described and results are reviewed with particular attent ion to the in vivo imaging of Pgp and MRP. Various detection assays provide information about the presence of drug efflux pumps at the mRNA and protei n levels. However, these methods do not yield information about the dynamic function of Pgp and MRP in vivo. For the study of Pgp- and MRP-mediared tr ansport, single-photon emission tomography (SPET) and positron emission tom ography (PET) are available. Technetium-99m sestamibi is a substrate for Pg p and MRP, and has been used in clinical studies for tumour imaging, and to visualize blockade of Pgp-mediated transport after modulation of the Pgp p ump. Other Tc-99m radiopharmaceuticals, such as Tc-99m-tetrofosmin and seve ral Tc-99-Q complexes, are also substrates for Ppp, but to date only result s from in vitro and animal studies are available for these compounds. Sever al agents, including [C-11]colchicine, [C-11]verapamil and [C-11]daunorubic in, have been evaluated for the quantification of Pgp-mediated transport wi th PET in vivo. The results suggest that radiolabelled colchicine, verapami l and daunorubicin are feasible substrates with which to image Pgp function in tumours. Uptake of [C-11]colchicine and [C-11]verapamil is relatively h igh in the chest area, reducing the value of both tracers for monitoring Pg p-mediated drug transport in rumours located in this region. In addition, i t has to be borne in mind that only comparison of Pgp-mediated transport of radioalabelled substrates in the absence and in the presence of Pgp blocka de gives quantitative information on Pgp-mediated pharmacokinetics, Leukotr ienes are specific substrates for MRP. Therefore, N-[C-11]acetyl-leukotrien e E-4 provides an opportunity to study MRP function non-invasively. Results obtained in MRP2 mutated GY/TR rats have demonstrated visualization of MRP -mediated transport. This tracer permits the study of MRP transport functio n abnormalities in vivo, e.g, in Dubin-Johnson patients, who are MRP2, gene deficient. Results obtained show the feasibility of using SPET and PET to study the functionality of MDR transporters in vivo.