The penetration of misonidazole into spontaneous canine tumours

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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 tumors and the resulting tumor concentrations were measured by HPLC [high pressure liquid chromatography] analysis. In 4 dogs serial biopsy specimens were obtained up to 5 h. With the exception of a brain tumor, the tumor concentrations ranged between 47% and 95% of the plasma concentration, most of the values falling within the range 50-70%. Concentrations in the brain tumor were markedly lower. Barbiturate anesthesia was necessary for the removal of the serial biopsy specimens, and the effects of sodium pentobarbitone anesthesia on the pharmacokinetics of MIS were investigated in 2 dogs. After barbiturate anesthesia peak plasma concentrations 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; MIS concentrations approached those of the plasma, whereas the metabolite concentrations were considerably lower (0-58% of the plasma concentration).