Studies of the pharmacokinetic properties of nimorazole

Abstract

The pharmacokinetics of the hypoxic radio-sensitizer nimorazole were studied in 19 individuals after single oral doses of between 0.5-3.5 g. HPLC measurements showed, after a rapid absorption, a linear relationship between peak plasma concentration and given dose. Mean elimination half life was 3.1 h. A tendency to a dose-dependent variation in the apparent volume of distribution, total body clearance and elimination half life suggest non-linear pharmacokinetics of nimorazole. Tumour concentrations measured in 5 patients gave tumour/plasma ratios between 0.8-1.3. No toxicity was observed. The results indicate that nimorazole may have potential as a clinically useful hypoxic radiosensitizer.

A comparative investigation of nimorazole and misonidazole as hypoxic radiosensitizers in a C3H mammary carcinoma in vivo

“…Measurement of drug concentrations.-Blood samples were obtained by open-heart puncture after killing the mice by cervical dislocation, Plasma concentrations were measured by reversed-phase high-pressure liquid chromatography (HPLC) (Overgaard et al, 1983) by injecting 25 ,lI of the sample in a nucleosil 10 Fm C18 column at a flow of 2 ml/min.…”

“…Furthermore, comparable data indicate that nimorazole has considerably less acute or chronic toxicity in dogs, and nimorazole seems to be even less toxic in dogs than metronidazole (Roche, unpub-lished data; Farmltalia, Carlo Erba, unpublished data). In humans nimorazole has been given in doses up to 25 g in 10 days without causing peripheral neuropathy or other severe side effects (Overgaard et al, 1983). Thus nimorazole seems to be considerably better tolerated than MISO, and on the basis of largeanimal toxicity it may be tolerated as well as metronidazole (Flagyl) which can be given in daily doses of 6 g/m2 and in total doses up to 100 g (Kapp et al, 1982;Karim, 1978;Urtasun et al, 1975).…”

“…However, if the lack of significant toxicity can be established, it might be a more acceptable drug with a better therapeutic ratio in clinical treatment. Further studies to explore the potential of nimorazole as a hypoxic radiosensitizer in clinical radiotherapy have therefore been started (Overgaard et al, 1983).…”

“…This group of drugs are mainly anti-trichomonal agents of which metronidazole (Flagyl) was the first to be tested as a hypoxic radiosensitizer (Fowler et al, 1976;Karim, 1978;Urtasun et al, 1975), but which has a sensitizing ability which is probably too low for widespread clinical utility. Another similar drug with a toxicity apparently equal to or less than metronidazole (Farmitalia, Carlo Erba, unpublished results) is nimorazole (1-(N-3-ethylmorpholine)-5-nitro-imidazole), which is also widely used as an anti-microbial agent (Overgaard et al, 1983). Although sporadically tested as a hypoxic radiosensitizer and found to be more potent than metronidazole (Adams et al, 1979b;Denekamp et al, 1982), relatively little attention has been paid to this drug.…”

Synergistic Cancer Therapeutic Effects of Locally Delivered Drug and Heat Using Multifunctional Nanoparticles

“…These results demonstrated that the combined DOX and photothermal treatments were more cytotoxic than chemotherapy or photothermal treatment alone. This synergistic effect was probably ascribed to enhanced cytotoxicity of DOX at elevated temperatures [18][19][20] and a higher heat sensitivity for the cells exposed to DOX than for the cells not exposed to DOX. [ 12 ] During the treatments, we also measured the body weight of the mice, since high toxicity usually leads to weight loss.…”