Pharmacokinetics and Tissue Disposition of Indole-3-carbinol and Its Acid Condensation Products after Oral Administration to Mice

• Published in: Clinical cancer research 2004-08, Vol.10 (15), p.5233-5241
• Main Authors: ANDERTON, Mark J, MANSON, Margaret M, VERSCHOYLE, Richard D, GESCHER, Andreas, LAMB, John H, FARMER, Peter B, STEWARD, William P, WILLIAMS, Marion L
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Anticarcinogenic Agents - administration & dosage; Anticarcinogenic Agents - blood; Anticarcinogenic Agents - pharmacokinetics; Antineoplastic agents; Biological and medical sciences; Chromatography, High Pressure Liquid; Chromatography, Liquid; Female; Free Radical Scavengers - administration & dosage; Free Radical Scavengers - blood; Free Radical Scavengers - pharmacokinetics; Indoles - administration & dosage; Indoles - blood; Indoles - pharmacokinetics; Liver - metabolism; Medical sciences; Mice; Models, Chemical; Oxygen - metabolism; Perfusion; Pharmacology. Drug treatments; Time Factors; Tissue Distribution; Tumors
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-04-0163

Indole-3-carbinol (I3C) and 3,3′-diindolylmethane (DIM) are promising cancer chemopreventive agents in rodent models, but there is a paucity of data on their pharmacokinetics and tissue disposition. The disposition of I3C and its acid condensation products, DIM, [2-(indol-3-ylmethyl)-indol-3-yl]indol-3-ylmethane (LTr 1 ), indolo[3,2b]carbazole (ICZ) and 1-(3-hydroxymethyl)-indolyl-3-indolylmethane (HI-IM) was studied, after oral administration of I3C (250 mg/kg) to female CD-1 mice. Blood, liver, kidney, lung, heart, and brain were collected between 0.25 and 24 h after administration and the plasma and tissue concentrations of I3C and its derivatives determined by high-performance liquid chromotography. I3C was rapidly absorbed, distributed, and eliminated from plasma and tissues, falling below the limit of detection by 1 h. Highest concentrations of I3C were detected in the liver where levels were approximately 6-fold higher than those in the plasma. Levels of DIM, LTr 1 , and HI-IM were much lower, although they persisted in plasma and tissues for considerably longer. DIM and HI-IM were still present in the liver 24 h after I3C administration. Tissue levels of DIM and LTr 1 were found to be in equilibrium with plasma at almost every time point measured. In addition to acid condensation products of I3C, a major oxidative metabolite (indole-3-carboxylic acid) and a minor oxidative metabolite (indole-3-carboxaldehyde) were detected in plasma of mice after oral administration of I3C. ICZ was also tentatively identified in the liver of these mice. This study shows for the first time that, after oral administration to mice, I3C, in addition to its acid condensation products, is absorbed from the gut and distributed systemically into a number of well-perfused tissues, thus allowing the possibility for some pharmacological activity of the parent compound in vivo .