Pharmacokinetic studies using multiple administration of RO 03-8799, a 2-nitroimidazole radiosensitizer

It has been shown that the propanolamine 2-nitroimidazole Ro 03-8799, is about an order of magnitude more efficient than misonidazole as a radiosensitizer in vitro, which is more than its electron affinity would predict. However, in vivo studies have so far shown only a minimal improvement compared to misonidazole. One reason for this could be that diffusion to the site of action in the hypoxic cell is restricted by the short half-life in the mouse and the net positive charge carried by the drug at physiological pH. Ways of maintaining a constant blood or tumor concentration over a period of 1--2 hours were investigated so that the tumor response could be assessed after this time. Initial experiments used multiple intraperitoneal or intravenous injections, for which the amount of drug required can be calculated theoretically provided sufficient pharmacokinetic data are available. Later experiments using continuous infusion of the drug were aimed at maintaining the gross tumor concentration equal to that found at the time of peak sensitization following a single administration. Results will be presented using each of these approaches. The technical feasibility and advantages of each method, together with general problems associated with interpreting any radiobiological results obtained using this approach will be discussed.