Comparative physiological disposition of ellipticine in several animal species after intravenous administration

Abstract

The physiological dispositon of ellipticine (NSC 71795) has been studied in the mouse, rat, dog and monkey after administration of [1-14C]ellipticine at 6 mg/kg iv (3 mg/kg to monkey). Ellipticine was very rapidly distributed from the blood of all species and was deposited in tissues. The rate of elimination of ellipticine from blood was species-dependent, half-times ranging from 22 min in mouse to 210 min in rat, and probably reflected the rate of metabolism of the drug. The rate of elimination of metabolites from blood was also species-dependent, half-times ranging from 140 min in mouse to 380 min in rat, and probably reflected the rate of biliary secretion of the metabolites. Ellipticine was widely but not uniformly distributed throughout the tissues including brain, and some of the highest concentrations of drug and metabolites were in liver, which is probably the primary site of metabolism. The concentrations of ellipticine and metabolites in tissues were species-dependent, correlating with species differences in rates of metabolism and excretion. All species excreted 80% of the dose via the fecal route and 10% via the urinary route, primarily as metabolites during the first 24 hr after dosing. Metabolites entered the gastrointestinal tract by biliary secretion and ellipticine entered by an ion-trapping mechanism. Evidence is presented that the major pathway for ellipticine metabolism in rat was to 9-hydroxyellipticine, which did not accumulate in liver but was conjugated to its glucuronide and sulfate, which were secreted in bile. Other pathways involved hydroxylation and glucuronide conjugation. The pharmacokinetics of ellipticine are correlated with its toxic side effects, such as acute hypotention and neurological symptoms. They are also correlated with its potential as an antitumor agent, such as its ability to achieve values for the area under the curve of concentration vs. time (CXt) in tumors, which would be adequate for therapy. Based upon these correlations, the drug should be administered in the clinic by iv infusion, or, provided its bioavailability is found to be satisfactory, by the oral route.