Pharmacologic Characterization of Teroxirone (Henkel Compound) in Animals and Humans
Teroxirone (T, Henkel compound) is a triepoxide antitumour agent first studied in Europe. A more soluble preparation is being evaluated in the U.S. We have studied the disposition and metabolism of T in rabbits, rats and humans. We have developed an hplc assay based on derivatisation of T with diethyldithiocarbamate (DDC). T was analysed following extraction from biological fluids, derivatization with DDC, and normal phase hplc analysis. Following rapid i.v. infusion to patients, plasma disappearance is characterized by a one-compartment open model with mean values for t1/2, total body clearance and volume of distribution of 1.4min, 5.7ℓ/min, and 13ℓ, respectively. When T is administered by i.v. infusion (60–240min), plateau plasma concentrations are rapidly achieved, followed by rapid disappearance at the end of infusion. T is rapidly metabolised by hepatic, but not lung, microsomal preparations. Metabolism is NADPH independent and is inhibited by cyclohexene oxide. Epoxide hydrolysis products were detected in microsomal preparations and rabbit urine following administration of T. T cytotoxicity to human tumour cell lines in culture is abolished in the presence of 9,000 x g rat liver preparations, and is restored by the addition of cyclohexene oxide to incubation mixtures.