METABOLISM AND DISPOSITION STUDIES OF 9-HYDROXYELLIPTICINE AND 2-METHYL-9-HYDROXYELLIPTICINIUM ACETATE IN ANIMALS

Abstract

Radiolabeled 9-hydroxyellipticine (i.v. and i.p. routes) and the corcorresponding radioactive quaternary salt, 2-methyl-9-hydroxyellipticinium acetate (i.v. route) were administered to mice. Tissue distribution was then followed up to 64 h by autoradiography. Both drugs accumulated in the kidneys, lungs and liver; 9-hydroxyellipticine also accumulated in the spleen and bone marrow. The quaternary salt was concentrated in the gastrointestinal walls and the salivary and thyroid glands; none was found in the brain. Metabolic studies after administration of these antitumor drugs to rats and mice showed that 9-hydroxyellipticine is extensively metabolized, mainly to its glucuronide. Under these experimental conditions, the ellipticinium derivative was excreted unchanged in the bile (70%) and in the urine (30%). Pharmacokinetic studies in mice using radioactivity measurements or selective extraction followed by spectrofluorometric quantitation showed that blood levels drop very rapidly during the distribution phase followed by a much slower disposition phase, with a half-life of about 30 h for the quarternary salt.