The effect of radiosensitizers on the pharmacokinetics of melphalan and cyclophosphamide in the mouse

Abstract

Misonidazole (MISO) has been shown to affect the pharmacokinetics of both cyclophosphamide (CY) and melphalan (MEL) in WHT mice resulting in increased plasma levels of the cytotoxic drugs. The effect is not solely due to the reduction in body temperature observed with large single doses of MISO, as a change in MEL pharmacokinetics was still observed when the mice were maintained at 37 degrees C. Inhibition of cytotoxic drug metabolism may also be a possible mechanism. Such a pharmacokinetic effect could account for part of the potentiation of MEL and CY action observed in tumours with large single doses of MISO. However, a chronic low dosing schedule of MISO did not affect the plasma half-life of either cytotoxic drug, although a significant potentiation of each drug in combination with a chronic MISO dose has been obtained in some tumours. These results suggest that potentiation of chemotherapeutic drug action by MISO in the clinical situation is unlikely to be due to changes in drug pharmacokinetics.