Single-dose pharmacokinetics and tolerability of absorption-enhanced 3,3'-diindolylmethane in healthy subjects

Abstract

We have completed a single ascending dose clinical study of the proposed chemopreventive agent 3,3'-diindolylmethane (DIM). The study agent was nutritional-grade, absorption-enhanced BioResponse 3,3'-diindolylmethane (BR-DIM). We determined the safety, tolerability, and pharmacokinetics of single doses of BR-DIM in drug-free, non-smoking, healthy men and women. Groups of four subjects were enrolled for each dose level. After randomization, one subject in each group received placebo whereas three received active BR-DIM. The doses administered were 50, 100, 150, 200, and 300 mg, with the 300-mg dose repeated in an additional group. No BR-DIM-related adverse effects were reported at doses up to 200 mg. At the 300-mg dose, one of six subjects reported mild nausea and headache and one also reported vomiting. Only the latter effect was judged as probably related to the study agent. Analysis of serial plasma samples showed that only one subject at the 50-mg dose had detectable concentrations of DIM. The single 100-mg dose of BR-DIM resulted in a mean maximum plasma concentration (C(max)) of 32 ng/mL and a mean area under the curve (AUC) of 128 h ng/mL, and a single 200-mg dose produced a mean C(max) of 104 ng/mL and a mean AUC of 553 h ng/mL. The single 300-mg dose of BR-DIM resulted in a mean C(max) of 108 ng/mL and a mean AUC of 532 h ng/mL. We conclude that BR-DIM is well tolerated at single doses of up to 200 mg, and that increasing the dose to 300 mg did not result in an increase in C(max).

Figures

Figure 1. Mean Plasma Concentration Profiles for Single Doses of BR-DIM

Values are the actual plasma concentrations of DIM for the single subject at the 50 mg BR-DIM dose with measurable plasma concentrations, and the mean values for all dosed subjects for the 100, 150, and 200 mg doses (n=3 per dose) and the 300 mg dose (n=6) of BR-DIM.

Figure 2. Dose-Dependency of DIM Pharmacokinetics following BR-DIM and I3C Administration

The observed Cmax and the calculated AUC for DIM from administration of different doses of BR-DIM (this study, Panels A and C, respectively) or from different doses of I3C (Ref. , Panels B and D, respectively). Values from subjects receiving BR-DIM (Panels A and C) are from a single subject at the 50 mg dose, and the mean values for 3 subjects at the 100, 150, and 200 mg doses and 6 subjects at the 300 mg dose. For subjects receiving I3C (Panels B and D), values shown are means of 4 subjects from the 400, 600, and 800 mg doses; 3 subjects at the 1000 mg dose, and 8 subjects at the 1200 mg dose.

Figure 3. Relationship Between DIM Plasma Concentrations and Adverse Events

Points represent the Cmax and AUC for all subjects, with each subject’s dose of BR-DIM denoted as labeled. Filled symbols denote the 6 subjects reporting adverse effects, as listed in Table 2.