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The role of dexamethasone in the modification of misonidazole pharmacokinetics
Abstract:
A review of misonidazole pharmacokinetics in 83 consecutive patients treated for tumours other than glioma has shown that among patients not receiving enzyme-inducing agents the plasma elimination half life is lower in patients taking steroids. Such a difference is not seen if patients already taking enzyme inducers are given steroids. Five further patients with carcinoma of the lung, treated with radiation over a period of 3 weeks, have been studied in greater detail. Misonidazole, in oral dose of 1 gm-2, was given in conjunction with the first and last radiotherapy fractions, and dexamethasone, in a divided daily dose of 8 mg, was given throughout the radiation treatment, commencing after the first treatment. Misonidazole pharmacokinetics were studied at each administration. Following the dexamethasone treatment period there was a 25% reduction in misonidazole plasma elimination half life, a 24% reduction in plasma AUC0-00, and a 38% increase in 24 h urinary excretion (all changes being statistically significant--P less than 0.005). No changes were observed in the plasma AUC0-24 and urinary excretion of the major metabolite desmethylmisonidazole. Glomerular filtration rates in one patient, before and after treatment with dexamethasone, remained unchanged. These results suggest that the effect of dexamethasone on misonidazole kinetics is not related to an enhancement of demethylation.
Insights
Steroids reduce misonidazole
Area of Science:
- Pharmacology
- Oncology
- Radiotherapy
Background:
- Misonidazole is a hypoxic cell radiosensitizer used in cancer treatment.
- Steroids, like dexamethasone, are often co-administered with cancer therapies.
- The interaction between misonidazole and steroids requires further investigation.
Purpose of the Study:
- To investigate the effect of dexamethasone on misonidazole pharmacokinetics in cancer patients.
- To determine if dexamethasone alters misonidazole's elimination or metabolism.
Main Methods:
- Review of misonidazole pharmacokinetics in 83 patients.
- Detailed pharmacokinetic study in 5 lung cancer patients receiving misonidazole and dexamethasone concurrently with radiotherapy.
- Analysis of misonidazole plasma levels, half-life, AUC, and urinary excretion before and after dexamethasone treatment.
Main Results:
- Steroid use was associated with a lower misonidazole plasma elimination half-life in patients not on enzyme inducers.
- Dexamethasone treatment significantly reduced misonidazole's plasma elimination half-life (25%) and AUC (24%).
- Dexamethasone significantly increased misonidazole's 24-hour urinary excretion (38%) without affecting its major metabolite, desmethylmisonidazole.
Conclusions:
- Dexamethasone significantly alters misonidazole pharmacokinetics, primarily by increasing its elimination.
- The observed changes suggest that dexamethasone enhances misonidazole clearance through mechanisms other than demethylation.
- These findings have implications for optimizing misonidazole dosing in combination cancer therapy.