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Pharmacological characterization of teroxirone, a triepoxide antitumor agent, in rats, rabbits, and humans
Abstract:
Teroxirone is an experimental triepoxide antitumor agent currently undergoing evaluation in clinical trials. We have developed an assay based on derivatization with diethyldithiocarbamate followed by normal-phase high-performance liquid chromatographic analysis. When 14C-labeled teroxirone is administered to rabbits by rapid i.v. infusion, plasma disappearance of parent drug is very rapid (t1/2 less than 5 min), while plasma 14C-labeled drug equivalents are eliminated at a much slower rate (t1/2 greater than 60 min). Twenty-four-hr urinary recovery of parent drug is less than 1%, while recovery of 14C total radioactivity is 60 to 70%. Rapid plasma elimination (t1/2 less than 5 min) and total body clearance (greater than 5 liters/min) are observed following rapid i.v. administration of teroxirone to humans. When teroxirone is administered to humans at constant rates of infusion, plateau concentrations are rapidly achieved and maintained during infusion. Plasma concentrations rapidly decrease upon cessation of infusion. Less than 1% parent drug is recovered in 24-hr urine. Teroxirone is relatively stable in fresh human plasma and whole blood. Teroxirone is metabolized by rat liver, but not lung, microsomal preparations by an NADPH-independent pathway. Epoxide hydrolysis metabolites are detected in microsomal incubations, and cyclohexene oxide inhibits teroxirone metabolism, suggesting that epoxide hydrase may be responsible for teroxirone biotransformation. Cytotoxicity of teroxirone against continuous human tumor cell lines is abolished in the presence of 9000 X g rat liver supernatant preparations but partially restored when cyclohexene oxide is added to incubation mixtures.
Insights
Teroxirone, an antitumor agent, is rapidly eliminated from plasma in humans and rabbits. Its metabolism involves epoxide hydrolysis, likely by epoxide hydrase, and its cytotoxicity is reduced by liver enzymes.
Area of Science:
- Pharmacology
- Drug Metabolism
- Biochemistry
Background:
- Teroxirone is an experimental triepoxide antitumor agent.
- Its pharmacokinetic and metabolic profiles are crucial for understanding its efficacy and safety.
Purpose of the Study:
- To characterize the pharmacokinetic profile of teroxirone in rabbits and humans.
- To investigate the metabolic pathways and enzymes involved in teroxirone biotransformation.
- To assess the impact of metabolism on teroxirone's cytotoxicity.
Main Methods:
- Development of a high-performance liquid chromatographic assay for teroxirone.
- Pharmacokinetic studies in rabbits and humans following intravenous administration.
- In vitro metabolism studies using rat liver and lung microsomes.
- Assessment of cytotoxicity in human tumor cell lines with and without metabolic activation.
Main Results:
- Teroxirone exhibits rapid plasma elimination (t1/2 < 5 min) and high total body clearance (> 5 L/min) in humans.
- Urinary recovery of parent teroxirone is minimal (< 1%) in both species.
- Metabolism in rat liver microsomes is NADPH-independent, suggesting epoxide hydrase involvement.
- Metabolism abolishes teroxirone's cytotoxicity, which can be partially restored by inhibiting epoxide hydrase.
Conclusions:
- Teroxirone is rapidly eliminated and extensively metabolized in vivo.
- Epoxide hydrase is likely the primary enzyme responsible for teroxirone biotransformation.
- Metabolic inactivation of teroxirone by liver enzymes reduces its antitumor activity.
