QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Anderton, M. J. Articles by Mager, D. E. Search for Related Content PubMed PubMed Citation Articles by Anderton, M. J. Articles by Mager, D. E.

PHYSIOLOGICAL MODELING OF FORMULATED AND CRYSTALLINE 3,3'-DIINDOLYLMETHANE PHARMACOKINETICS FOLLOWING ORAL ADMINISTRATION IN MICE

Departments of Biochemistry and Cancer Studies, University of Leicester, Leicester, United Kingdom (M.J.A., M.M.M., R.V., A.G., W.P.S., M.L.W.); and National Institute on Aging, Gerontology Research Center, Baltimore, Maryland (M.L.W., D.E.M.)

3,3'-Diindolylmethane (DIM) is a naturally occurring indole, which is currently under investigation as a potential chemopreventive agent. The concentrations of DIM in plasma, liver, kidney, lung, heart, and brain tissues were determined following oral administration of two different formulations to mice (250 mg/kg). Mice were sacrificed periodically from 0 to 24 h after administration of either a crystalline or an absorption-enhanced formulation (Bio-Response-DIM; Indolplex) of DIM, and plasma and tissue concentrations were determined by high-performance liquid chromatography (UV detection, 280 nm). A physiologically based pharmacokinetic (PBPK) model was developed to characterize the pharmacokinetic properties of the two different formulations. The final model included parameters reflecting linear first-order absorption, systemic clearance, and distributional clearance in the remainder compartment, which were considered independent of formulation. All pharmacokinetic profiles from the two formulations were fitted simultaneously to estimate unknown model parameters. Plasma and tissue concentration-time profiles exhibited a rapid rise to peak values at 0.5 to 1 h, followed by a polyexponential decline with an extended terminal phase. These profiles were well described by the final model and unknown parameters were estimated with relatively low coefficients of variation. Relative drug exposure and absorption parameters suggest that BioResponse-DIM exhibited approximately 50% higher bioavailability than the crystalline formulation. Clearance of DIM was estimated as 7.18 ml/h. This is the first study to characterize the pharmacokinetics of DIM in mice, and the established PBPK model should prove useful in the design and analysis of future preclinical studies aimed at evaluating the in vivo pharmacological effects of DIM.

This article has been cited by other articles:

				G. A. Reed, J. M. Sunega, D. K. Sullivan, J. C. Gray, M. S. Mayo, J. A. Crowell, and A. Hurwitz Single-Dose Pharmacokinetics and Tolerability of Absorption-Enhanced 3,3'-Diindolylmethane in Healthy Subjects Cancer Epidemiol. Biomarkers Prev., October 1, 2008; 17(10): 2619 - 2624. [Abstract] [Full Text] [PDF]

				H. J. Cho, M. R. Seon, Y. M. Lee, J. Kim, J.-K. Kim, S. G. Kim, and J. H. Y. Park 3,3'-Diindolylmethane Suppresses the Inflammatory Response to Lipopolysaccharide in Murine Macrophages J. Nutr., January 1, 2008; 138(1): 17 - 23. [Abstract] [Full Text] [PDF]

				Y. Li, Z. Wang, D. Kong, S. Murthy, Q. P. Dou, S. Sheng, G. P. V. Reddy, and F. H. Sarkar Regulation of FOXO3a/beta-Catenin/GSK-3beta Signaling by 3,3'-Diindolylmethane Contributes to Inhibition of Cell Proliferation and Induction of Apoptosis in Prostate Cancer Cells J. Biol. Chem., July 20, 2007; 282(29): 21542 - 21550. [Abstract] [Full Text] [PDF]

				G. A. Reed, D. W. Arneson, W. C. Putnam, H. J. Smith, J. C. Gray, D. K. Sullivan, M. S. Mayo, J. A. Crowell, and A. Hurwitz Single-Dose and Multiple-Dose Administration of Indole-3-Carbinol to Women: Pharmacokinetics Based on 3,3'-Diindolylmethane Cancer Epidemiol. Biomarkers Prev., December 1, 2006; 15(12): 2477 - 2481. [Abstract] [Full Text] [PDF]

				M. M.R. Bhuiyan, Y. Li, S. Banerjee, F. Ahmed, Z. Wang, S. Ali, and F. H. Sarkar Down-regulation of Androgen Receptor by 3,3'-Diindolylmethane Contributes to Inhibition of Cell Proliferation and Induction of Apoptosis in Both Hormone-Sensitive LNCaP and Insensitive C4-2B Prostate Cancer Cells. Cancer Res., October 15, 2006; 66(20): 10064 - 10072. [Abstract] [Full Text] [PDF]