Pharmacological Characterization of Teroxirone, a Triepoxide Antitumor Agent, in Rats, Rabbits, and Humans¹

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 (t_½ <5 min), while plasma ¹⁴C-labeled drug equivalents are eliminated at a much slower rate (t_½ >60 min). Twenty-four-hr urinary recovery of partent drug is <1%, while recovery of ¹⁴C total radioactivity is 60 to 70%. Rapid plasma elimination (t_½ <5 min) and total body clearance (>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 × g rat liver supernatant preparations but partially restored when cyclohexene oxide is added to incubation mixtures.