Pharmacokinetics and metabolism of the mixed-function hypoxic cell sensitizer prototype RSU 1069 in mice

Summary

RSU 1069 is a leading compound in the class of mixed-function hypoxic cell sensitizers. Possessing an alkylating aziridine function as well as a nitro group, it represents an important prototype molecule for new sensitizer development. Using a novel HPLC assay for RSU 1069 and its metabolites with a cyanopropyl column, we studied the detailed pharmacokinetics and metabolism of this drug in mice. An i.v. dose of 100 mg kg^-1 produced peak plasma concentrations of about 100 μg ml^-1. Absorption was rapid after i.p. injection but peak plasma, concentrations were some three- to fourfold lower, giving an i.p. bioavailability of 55%. The elimination t_1/2 was route-dependent; e.g. after 50 mg kg^-1 the t_1/2 was 37.2 and 22.4 min for the i.v. and i.p. routes respectively (P<0.001). There was also an indication of dose-dependent kinetics, with a 37% increase in elimination t_1/2 when the i.p. dose was doubled from 50 to 100 mg kg^-1. Oral bioavailability was low. The volume of distribution was 0.65–1.31 ml g^-1 at 50 mg kg^-1, but tissue penetration was limited. Brain/plasma ratios ranged from 9.3% to 66.8%, while the mean steady-state tumour/plasma ratio was 28.4%, a value considerably less than the 80%–100% ratios occurring with the neutral 2-nitroimidazole misonidazole. About 18% and 8% of a dose were excreted as the parent drug and the ring-opened hydrolysis product (RSU 1137) in the 8 h urine, indicating the likelihood of extensive metabolism via aziridine-ring remooval and nitroreduction. RSU 1137 was also detected in mouse plasma and tissues and, in contrast to the aziridine ring-intact parent compound, gave tumour/plasma ratios of 100%. These studies should provide a pharmacokinetic basis for the evaluation and development of improved mixed-function sensitizers.