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Single-Dose and Multiple-Dose Administration of Indole-3-Carbinol to Women: Pharmacokinetics Based on 3,3'-Diindolylmethane

Departments of ¹ Internal Medicine, ² Pharmacology, Toxicology, and Therapeutics, and ³ Dietetics and Nutrition, ⁴ Center for Biostatistics and Advanced Informatics, and ⁵ Kansas Masonic Cancer Research Institute, University of Kansas Medical Center, Kansas City, Kansas; ⁶ Midwest Research Institute, Kansas City, Missouri; and ⁷ Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland

Requests for reprints: Gregory A. Reed, University of Kansas Medical Center, MS 1018, 3901 Rainbow Boulevard, Kansas City, KS 66160. Phone: 913-588-7513. E-mail: greed{at}kumc.edu

We have completed a phase I trial in women of the proposed chemopreventive natural product indole-3-carbinol (I3C). Women received oral doses of 400, 600, 800, 1,000, and 1,200 mg I3C. Serial plasma samples were analyzed by high-performance liquid chromatography-mass spectrometry for I3C and several of its condensation products. I3C itself was not detectable in plasma. The only detectable I3C-derived product was 3,3'-diindolylmethane (DIM). Mean C_max for DIM increased from 61 ng/mL at the 400-mg I3C dose to 607 ng/mL following a 1,000-mg dose. No further increase was observed following a 1,200-mg dose. A similar result was obtained for the area under the curve, which increased from 329 h ng/mL at the 400-mg dose to 3,376 h ng/mL after a 1,000-mg dose of I3C. Significant interindividual quantitative variation was seen in plasma DIM values within each dosing group, but the overall profiles were qualitatively similar, with no quantifiable DIM before dosing, t_max at 2 h, and DIM levels near or below 15 ng/mL (the limit of quantitation), by 24 h. Different results were obtained for 14 subjects who received a 400-mg dose of I3C after 8 weeks of twice-daily I3C dosing. Although the predose sampling occurred at least 12 h after the last known ingestion of I3C, 6 of 14 subjects exhibited C_max for DIM in their predose plasma. Despite this high initial value, plasma DIM for all subjects decreased to near or below the limit of quantitation within the 12-h sampling period. Possible reasons for this disparity between apparent t_1/2 of DIM and the high predose values are discussed. (Cancer Epidemiol Biomarkers Prev 2006;15(12):2477–81)

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