Compartmental modelling of the breast cancer resistance protein (BCRP/ABCG2) in drug transport

Objective: The human breast cancer resistance protein (BCRP/ABCG2) of an ATP-binding cassette half-transporter is resistant to topotecan (TPT) a semi-synthetic derivative of camptothecin. Over-expression of BCRP is linked with high levels of resistance to the anti-cancer agent TPT by promoting drug efflux. To investigate this efflux pump mechanism, a compartmental model for the in vitro uptake kinetics of TPT has been extended from a previously published model. The new model describes the drug activity and delivery of the pharmacologically active form to the DNA target as well as the elimination of drug from the cytoplasm via the active pump. Results: Validation of the proposed model is achieved using scanning-laser microscopy data from live human breast cancer cells (MCF-7 cell line). The experiment used to collect these data imposes an output structure on the model that corresponds to the functions of the variables that can be directly observed (total concentrations of TPT in extracellular medium, cytoplasm and nucleus). Before estimating the unknown model parameters from the collected data it is essential to determine parameter uniqueness (or otherwise) from this imposed output structure. This determination is formally performed as a structural identifiability analysis, which demonstrates that all of the unknown model parameters are uniquely determined by the output structure corresponding to the real experiment. Conclusions: The fitted model has shown that, as the concentration of the free transporter increases, the concentration of the active form of TPT bound to the transporter increases in the cell membrane, additionally, it reaches saturation at a higher rate than other compartments. However, the concentration of the inactive form of TPT bound to the transporter is at a lower concentration in the cell membrane compared to the active form. Moreover, the model allows in silico estimations and predictions of the relationship between the target binding and the dose, with different expressions of the drug resistance protein, leading to the possibility of the design of optimal dosing regimens