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Pharmacokinetics and toxicology of continuously infused nitroimidazoles
Abstract:
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.
Insights
Continuous infusion of SR-2508 and misonidazole (MISO) in mice showed that SR-2508
Area of Science:
- Pharmacology and Toxicology
- Drug Delivery Systems
- Cancer Research
Background:
- Nitroimidazoles are investigated as potential radiosensitizers and hypoxia-targeting agents in cancer therapy.
- Continuous infusion offers an alternative administration route for nitroimidazoles, potentially altering their pharmacokinetic and toxicological profiles.
- Understanding the relationship between drug exposure, pharmacokinetics, and toxicity is crucial for optimizing therapeutic strategies.
Purpose of the Study:
- To compare the pharmacokinetics and toxicology of misonidazole (MISO) and SR-2508 administered via continuous intraperitoneal infusion in mice.
- To evaluate the impact of infusion rate and total drug dose on plasma and brain concentrations, and animal survival.
- To determine if drug toxicity is directly correlated with integral brain exposure under continuous infusion conditions.
Main Methods:
- Female C3H mice received continuous intraperitoneal infusions of MISO or SR-2508.
- Plasma and brain drug concentrations were quantified using High-Performance Liquid Chromatography (HPLC).
- Survival times were recorded, and pharmacokinetic parameters such as area under the curve (AUC) were calculated and correlated with toxicity.
Main Results:
- SR-2508 plasma concentration was dose-proportional to infusion rate, while MISO showed non-linear pharmacokinetics with increased half-life at higher doses.
- The brain-to-plasma concentration ratio for SR-2508 remained constant (~0.09) during prolonged infusions.
- MISO toxicity correlated with AUC, but SR-2508 toxicity was not directly related to AUC or brain exposure, with shorter survival observed despite lower brain concentrations.
Conclusions:
- Continuous infusion of SR-2508 results in a low and stable brain-to-plasma ratio, decoupling toxicity from integral brain exposure.
- The toxicity of SR-2508 under continuous infusion conditions is not solely predicted by brain concentrations, suggesting other mechanisms may be involved.
- Further investigation into the clinical application of continuously infused nitroimidazoles, considering their distinct pharmacokinetic and toxicological profiles, is warranted.