Pharmacokinetics and toxicology of continuously infused nitroimidazoles.
The pharmacokinetics and toxicology of misonidazole (MISO) and SR-2508 given by continuous intraperitoneal infusion were studied in female C3H mice. The survival (time to death) of animals receiving continuous infusions of SR-2508 and MISO was compared and related to plasma concentration, rate of infusion and total amount of drug delivered. Brain and plasma concentrations were determined by HPLC. For SR-2508, plasma concentration was directly proportional to the infusion rate. However, as the infusion rate of MISO was doubled, the plasma concentration of MISO increased approximately 6-fold, reflecting a substantial increase in the apparent half-life. The brain/plasma concentration ratio in animals infused for up to 6 days with SR-2508 remained constant, at approximately 0.09. For MISO the product of the plasma concentration and survival time (area under the curve (AUC) was constant and equal to approximately 50-mM-hrs. In contrast, the survival of animals infused with SR-2508 could not be directly related either to the AUC of plasma concentration X time or AUC brain concentration X time. At plasma concentrations of 0.08-1.5 mM, animals receiving SR-2508 survived approximately 3 times as long as animals exposed to a comparable plasma concentration of MISO. At higher plasma concentration (and infusion rates), the toxicity of SR-2508 relative to that of MISO was much greater. Even at the lowest infusion rates employed in this study, the survival of mice receiving SR-2508 was much shorter than would have been predicted if the toxicity of these two drugs were solely related to the integral brain exposure. The low brain/plasma concentration ratio of SR-2508 was maintained throughout long continuous exposures. Under these conditions the toxicity of the two drugs was not directly related to the integral brain exposure dose. Possible future clinical applications of continuously infused nitroimidazoles are discussed.
D000818:Animals; D001921:Brain / Q000378:metabolism; D017341:Etanidazole; D005260:Female; D051379:Mice; D008809:Mice, Inbred C3H; D008920:Misonidazole / Q000097:blood / Q000378:metabolism / Q000633:toxicity; D009593:Nitroimidazoles / Q000097:blood / Q000378:metabolism* / Q000633:toxicity; D011838:Radiation-Sensitizing Agents / Q000097:blood / Q000378:metabolism* / Q000633:toxicity
D009593:Nitroimidazoles; D011838:Radiation-Sensitizing Agents; D017341:Etanidazole; D008920:Misonidazole