Metabolism and disposition studies of 9-hydroxyellipticine and 2-methyl-9-hydroxyellipticinium acetate in animals.
Radiolabeled 9-hydroxyellipticine (iv and ip routes) and the corresponding radioactive quaternary salt, 2-methyl-9-hydroxyellipticinium acetate (iv route), were administered to mice. Tissue distribution was then followed up to 64 hours by means of 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 our experimental conditions, the ellipticinium derivative was excreted unchanged in the bile (70%) and in the urine (30%). Pharmacokinetic studies in mice using either radioactivity measurements or selective extraction followed by spectrofluorometric quantitation have shown that blood levels drop very rapidly during the distribution phase followed by a much slower disposition phase, with a half-life of about 30 hours for the quaternary salt.
D000470:Alkaloids / Q000378:metabolism*; D000818:Animals; D001345:Autoradiography; D001646:Bile / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D004611:Ellipticines / Q000008:administration & dosage / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D051379:Mice; D008811:Mice, Inbred DBA; D011817:Rabbits; D051381:Rats; D014018:Tissue Distribution
D000470:Alkaloids; D004611:Ellipticines; C027767:elliptinium; C008009:9-hydroxyellipticine