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Misonidazole toxicity and pharmacokinetics in mice: dependence on strain and size
Abstract:
The toxic side-effects of misonidazole (MISO) have been studied in two strains of mice over a wide weight range. The sensitivity of the mice, determined as the LD50 within 7 days of administration, varied by almost a factor of two. Differences were seen in the same strain, with heavy mice being most sensitive, and from strain to strain, with CBA mice being more susceptible than WHT albino mice. The toxicity of the MISO was closely related to a change in the peak blood levels, but showed no correlation with biological half-life. The tissue volume available for drug distribution appears to be reduced in large, heavy mice at high drug doses, and cannot be explained simply on the basis of drug exclusion from adipose tissue. For radiobiological studies with MISO doses of more than 0.5 mg/g it is recommended that it should be administered in a dosage that will give a known blood level of the drug, rather than simply by giving a constant dose based on body weight.
Insights
Mice sensitivity to misonidazole (MISO) toxicity varies by weight and strain. Heavy mice and CBA strain mice showed increased MISO susceptibility, impacting dosing strategies.
Area of Science:
- Pharmacology
- Toxicology
- Animal Models
Background:
- Misonidazole (MISO) is a hypoxic cell radiosensitizer.
- Understanding MISO's toxic side-effects is crucial for optimizing its clinical use.
- Mouse models are essential for preclinical evaluation of drug toxicity.
Purpose of the Study:
- To investigate the toxic side-effects of misonidazole (MISO) in different mouse strains and weight ranges.
- To determine factors influencing MISO toxicity, such as mouse weight, strain, and pharmacokinetic parameters.
- To provide recommendations for MISO administration in radiobiological studies.
Main Methods:
- Two mouse strains (CBA and WHT albino) were used.
- Mice were studied over a wide weight range.
- Lethal dose 50 (LD50) within 7 days was determined to assess toxicity.
- Peak blood levels and biological half-life of MISO were analyzed.
Main Results:
- MISO toxicity varied by almost a factor of two between mice.
- Heavier mice within the same strain were more sensitive to MISO.
- CBA mice exhibited higher susceptibility to MISO than WHT albino mice.
- Toxicity correlated with peak MISO blood levels but not biological half-life.
- Reduced tissue volume for drug distribution in heavy mice was observed.
Conclusions:
- Mouse weight and strain significantly influence misonidazole (MISO) toxicity.
- Peak blood concentration, not half-life, is a key determinant of MISO toxicity.
- Dosing of MISO should be based on achieving known blood levels, especially for radiobiological studies exceeding 0.5 mg/g.
- Further research into drug distribution in larger animals is warranted.