The role of the erythrocyte in antitumour drug transport

Abstract

The area of research on the substance-carrier capacity of the erythrocyte is rather limited and it remains difficult to estimate the impact of erythrocyte drug level monitoring in the clinic. Although equilibrium between blood and tissues based on the dissolution of compounds in the plasma water phase is often used in kinetic models, other models suggest that tissue levels correspond more closely to the protein-bound fraction than to the free fraction. For erythrocytes, the same may be true: tissues on the other side of capillary endothelium, or the capillary endothelium itself, may be more exposed to compounds accumulated on/in these cells. Since the introduction of the measurement of sediment (MESED) device, 100 µl of almost pure erythrocytes can be isolated with only 3.4 % trapped plasma. These RBCs are unwashed and thus maintained in their natural environment, without disruption of the normal equilibrium existing between red cells and plasma in whole blood. The first studies with ifosfamide and metabolites show that only minor chemical changes result in large changes of partitioning of the drugs between erythrocytes and plasma (chapter 1). While there is little detailed knowledge of the processes involved in uptake, transport and release, available data indicate a significant capacity of erythrocyte mediated substance transport.

Various anticancer agents can induce severe shape deformations of the erythrocyte resulting in decreased membrane deformability, which could be of importance in the microcirculation when the erythrocyte must deform to negotiate its entrance into narrow capillaries (chapter 2). It is difficult to estimate the impact of shape changes on the in vivo behaviour of anticancer drugs, but they could occasionally have pathophysiological consequences.

Chapter 3 stresses the importance of therapeutic drug monitoring (TDM) in both red blood cells and plasma during clinical drug development of anticancer agents and in individualising therapy.

Data of plasma monitoring during several phase I/II trials (section III) raised questions which we tried to solve by performing in-vitro incubation studies with several cytotoxic drugs in human volunteer blood (section II). With the use of the MESED device and new validated analytical methods, it was possible to determine the partition ratios (concentration RBC/concentration plasma) of those drugs at different incubation concentrations, to look at gender differences and at the influence of smoking habits on the partition. The choice of the three tested anticancer drugs, docetaxel, gemcitabine and irinotecan, was inspired by several phase I/II clinical trials performed in our Department with those drugs. In some of these trials, we had the opportunity to collect also data on the red blood cell fraction and we compared these data with those generated during our in vitro experiments.

The results of this thesis are indicative for further studies concerning the role of the erythrocyte in the (in-)efficacy of anticancer agents. There is no serious limitation anymore for simultaneous RBC and plasma monitoring in routine sessions. We should utilize positive and/or negative effects of substance uptake, transport and delivery by erythrocytes in future cancer treatment and in the development of new anticancer drugs.