International journal of radiation biology and related studies in physics, chemistry, and medicine

Cellular uptake of misonidazole and analogues with acidic or basic functions.

PMID 3873433


Average intracellular concentrations of five radiosensitizers in hamster fibroblast-like V79-379A cells in vitro were measured by high performance liquid chromatography, varying the extracellular pH (pHe) and estimating the apparent intracellular pH from the distribution of 5,5-dimethyloxazolidine-2,4-dione. The intracellular: extracellular concentration ratio for the 2-nitroimidazole, misonidazole was constant at about 0.7 for pHe = 6.6-7.6, whereas the weak base, Ro 03-8799 (1-(2-nitro-1-imidazolyl)-3-N-piperidino-2-propanol) was concentrated intracellularly at pHe = 7.3-7.4 by a factor of 3.3, the factor increasing from about 0.8 at pHe = 6.0, to 7.5 at pHe = 7.85. The weak acid, azomycin (2-nitroimidazole) showed approximately constant uptake (factor 1.1) between pHe = 6.0-7.0, decreasing to 0.8 at pHe = 7.3 and 0.4 at pHe = 7.8. Measurements of intracellular uptake of Ro 31-0052 (the more hydrophilic and less basic 3'-hydroxypiperidino analogue of Ro 03-8799) and of Ro 31-0258 (3-(2-nitro-1-imidazolyl)propionic acid, a stronger acid than azomycin) were made for comparison. The results were compared with theoretical calculations of pH-induced concentration gradients; the time dependence of the uptake of the bases is not at present clearly understood. These measurements of uptake are broadly consistent with the distribution of misonidazole and Ro 03-8799 in human and animal tissues and provide a useful insight into the likely intracellular concentrations in the clinical use of Ro 03-8799 or other basic radiosensitizers. The measurements also resolve the apparent discrepancy in radiosensitizer efficiency for weak bases in vitro and in vivo which has been previously noted.

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2-Nitroimidazole, 98%