Abstract 2899: Multiple-dose phase 1 study of 3,3′-diindolylmethane (DIM): Pharmacokinetics and biological effects

Abstract

Abstract We have completed our examination of the safety, tolerability, pharmacokinetics, and effects of twice daily doses of 100 mg and 200 mg of 3, 3’-diindolylmethane (DIM) for four weeks. Healthy adult subjects self-administered an absorption-enhanced formulation of DIM (BR-DIM). Eight subjects received the low dose, and six subjects received the high dose of BR-DIM. Based on medical histories, physical examinations and a battery of blood and urine tests we concluded that BR-DIM in this dosing regimen was very well tolerated, with no significant adverse effects. The pharmacokinetics of DIM were determined at each dose for both the first dose and last dose of BR-DIM in these subjects. The first dose Cmax and AUC values obtained for the two doses were similar to the results of our previous single ascending dose study of BR-DIM. Surprisingly, after four weeks of twice daily dosing, the mean Cmax of DIM fell by 29% and 73% and the mean AUC fell by 46% and 71% in the low and high dose groups, respectively. Multiple daily dosing with BR-DIM clearly altered expression either of specific transporters or of enzymes that biotransform DIM, resulting in a marked decrease in bioavailability. This decreased systemic exposure, however, must be considered in light of the observed induction of CYP1A2, one of our primary biomarkers of effect. Mean CYP1A2 activity increased by 250% at the low dose and by 181% at the high dose, suggesting that effective concentrations of DIM or an active metabolite were achieved in the liver, and that this resulted in induction of hepatic CYP1A2. No effects of BR-DIM were seen on activities of CYPs 2C9, 2D6, or 3A4. The lack of systemic exposure to DIM could result either from induced hepatic metabolism of DIM or from increased biliary secretion of DIM. This proposal for the altered pharmacokinetics of DIM, allowing hepatic effects but not extrahepatic effects, is consistent with the very modest effects of BR-DIM we observed on peripheral blood lymphocyte GST activity, and suggests that the lymphocyte activity may not be an accurate surrogate for hepatic effects of DIM. The lack of significant change in the 2-hydroxyestrone:16α-hydroxyestrone ratio, judged by us to be a key biomarker of efficacy in our previous trial with the DIM precursor indole-3-carbinol, raises the possibility that the change in that ratio is based to a significant extent on extrahepatic hydroxylation of estrone, rather than modulation of hepatic estrogen metabolism. Supported by NCI N01 CN-35008-38 and P20RR021940. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2899.