The penetration of misonidazole and desmethylmisonidazole into brain tumours and other central nervous system tissues in man.

The concentration of drug after oral administration of 1 g misonidazole to patients undergoing neurosurgery has been studied in samples taken from intracerebral tumours, normal brain, cerebrospinal fluid and brain tumour cyst fluid. A total of 31 patients yielded samples at various times 2-8 h after drug administration. Results show a considerable range of tumour/plasma percentages but from about 2-5 h after drug administration this averaged between 65-80%. Normal brain and CSF showed similar good penetration but drug entry into cyst fluid was lower (30-50%). A further study with desmethylmisonidazole given to 11 additional patients showed a similar range of tumour penetration but lower concentrations in CSF and cyst fluid (10-20%). Low values were also seen in some but not all of the normal brain tissue samples. Necrotic tumour also had much lower concentrations than macroscopically viable tissue. These results are discussed in terms of their clinical relevance to sensitiser studies on patients with brain tumours with drugs of different lipophilicities.

The concentration of desmethylmisonidazole in human tumours and in cerebrospinal fluid.

The concentration of desmethylmisonidazole (DESMISO) was determined in 60 biopsy samples taken from 13 human tumours and in cerebrospinal fluid (CSF) from 8 patients after oral administration. In comparison with misonidazole (MISO), peak concentrations in plasma were reached at earlier times and half-lives were shorter, so that the area under the curve of plasma concentration with time (AUC) was reduced by 45%; the AUC of CSF concentration with time was reduced by 67%. Between 1 and 2 h after administration of DESMISO, concentrations in tumours were generally 85-90% of those of MISO estimated approximately 4 h after it was given. The two drugs when tested in equimolar concentrations have been found in laboratory experiment to be equally potent as hypoxic cell radiosensitizers. Recognizing the lower mol. wt of DESMISO and the trend to higher concentrations in the more necrotic areas of the tumours studied equal doses by weight of the two drugs given orally may give equal radiosensitization of hypoxic cells in human tumours.

The penetration of misonidazole into spontaneous canine tumours.

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).