The penetration of misonidazole into spontaneous canine tumours

Abstract

The hypoxic cell-radiosensitizing drug misonidazole (1-(2-nitroimidazol-1-yl)-3-methoxypropan -2 -ol, Ro 07-0582, MIS) was administered at a dose of 150 mg/kg i.v. to 6 dogs bearing spontaneous tumours, and the resulting tumour concentrations were measured to HPLC analysis. In 4 dogs it was possible to obtain serial biopsy specimens up to 5 h. With the exception of a brain tumour, the tumour concentrations ranged between 47% and 95% of the plasma concentration, most of the values falling within the range 50--70%. Concentrations in the brain tumour were markedly lower. Barbiturate anaesthesia was necessary for the removal of the serial biopsy specimens, and the effects of sodium pentobarbitone anaesthesia on the pharmacokinetics of MIS were investigated in 2 dogs. After barbiturate anaesthesia peak plasma concontrations were raised and the availability of MIS was increased, although the biological half-life remained unaltered. The metabolism of MIS to the O-demethylated metabolite, Ro 05-9963, was delayed initially. The concentrations of MIS AND Ro 05-9963 in cerebrospinal fluid were also recorded in these dogs, MIS concentrations were found to approach those of the plasma, whereas the metabolite concentrations were considerably lower (0--58% of the plasma concentration).