Immunosuppressants are drugs that are used to treat inflammatory diseases, organ transplantation rejection, and cancer. These drugs are given to patients as single drugs, in combination, or together with other medications to treat accompanying diseases. Several severe side effects may result due to drug-drug interactions. It is thus important to understand the underlying mechanisms to avoid unnecessary toxicities. A number of immunosuppressants depend on the renal transporter proteins for their excretion. The aim of this thesis was to contribute to the understanding of the mechanisms of renal immunosuppressant transport, their drug interactions, and their hyperuricemic complications. To achieve that, cells and membrane vesicles over-expressing renal transporters were used. Transport activities were measured via radio-labelled liquid scintillation counting or by high performance liquid chromatography. Kinetic analysis of transporter-mediated substrate/inhibitor interactions was performed, and immunosuppressant drug interactions at the organ level were investigated using isolated perfused rat kidneys. This thesis concluded that some of the drugs tested inhibited specific renal transport of immunosuppressants, which may be the underlying mechanism of reported toxicities. These drug combinations may be used in treating patients resistant to chemotherapy. In addition, other drugs induced renal transport, which may provide a better substitution to avoid toxicities due to drug-drug interactions.

Contains fulltext : 65588_renatrand.pdf (Publisher’s version ) (Open Access) Contains fulltext : 70955.pdf (Publisher’s version ) (Open Access)

Promotor : Russel, F.G.M. Co-promotores : Koenderink, J.B., Masereeuw, R.

RU Radboud Universiteit Nijmegen, 15 oktober 2008

173 p.