Metabolism and disposition studies of 9-hydroxyellipticine and 2-methyl-9-hydroxyellipticinium acetate in animals

• Published in: Cancer treatment reports Vol. 64; no. 8-9; p. 879
• Main Authors: Van-Bac, N, Moisand, C, Gouyette, A, Muzard, G, Dat-Xuong, N, Le Pecq, J B, Paoletti, C
• Format: Journal Article
• Language: English
• Published: United States 01-08-1980
• Subjects: Alkaloids - metabolism; Animals; Autoradiography; Bile - metabolism; Brain - metabolism; Ellipticines - administration & dosage; Ellipticines - metabolism; Kidney - metabolism; Liver - metabolism; Lung - metabolism; Mice; Mice, Inbred DBA; Rabbits; Rats; Tissue Distribution
• ISSN: 0361-5960

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.