title: Pharmacokinetic evaluation and in vitro-in vivo correlation (IVIVC) of novel methylene-substituted 3,3' diindolylmethane (DIM).
abstract: OBJECTIVE
  3,3'-Diindolylmethane (DIM) is the major in vivo product of the acid-catalyzed oligomerization of indole-3-carbinol present in cruciferous vegetables. 1, 1-bis (3'-indolyl)-1-(p-substituted phenyl) methanes [C-substituted diindolylmethanes (C-DIMs)] are a new class of anticancer compounds derived from indole 3-carbinol. Despite rapidly increasing knowledge regarding mechanisms responsible for the chemopreventive properties of DIM-C-pPhC6H5, there have been relatively few studies determining the absorption and pharmacokinetic properties of DIM-C-pPhC6H5 to explore its clinical utility.
  
  
  METHODS
  In this study, we assessed the solubility, lipophilicity and Caco-2 cell permeability of methylene-substituted DIM. Pharmacokinetic properties in rats were determined following i.v. and oral administration of a novel analog of DIM. Pharmacokinetic parameters were determined using non-compartmental and compartmental techniques with WinNonlin® 5.0 software. To explore potential In Vitro-In Vivo Correlation (IVIVC) between the in vitro permeability values, and the oral absorption pharmacokinetics, we employed deconvolution of i.v. and oral data using a three compartment Exact Loo-Riegelman method.
  
  
  RESULTS
  The oral absorption and disposition were described by a three compartment model with combined zero-order/Michaelis-Menten limited systemic uptake using differential equations, at physiologically relevant doses. The saturation model obtained accounts for a nonlinear change in C(max)/Dose, and the absolute bioavailability (0.13±0.06) was also dose dependent. The absorption rate profile of DIM-C-pPhC6H5 across Caco-2 cells was significantly different than in vivo.
  
  
  CONCLUSIONS
  The pharmacokinetic absorption model presented represents a useful basis for obtaining plasma level predictability for poorly bioavailable, highly lipophilic drugs, such as the DIM analog DIM-C-pPhC6H5.
authors.affiliation: College of Pharmacy and Pharmaceutical Sciences, Florida A & M University, Tallahassee, FL 32307, USA.
authors.forename: Apurva R
authors.initials: AR
authors.lastname: Patel
authors.forename: Shawn D
authors.initials: SD
authors.lastname: Spencer
authors.forename: Mahavir B
authors.initials: MB
authors.lastname: Chougule
authors.forename: Stephen
authors.initials: S
authors.lastname: Safe
authors.forename: Mandip
authors.initials: M
authors.lastname: Singh
mesh_terms: D000284:Administration, Oral; D000704:Analysis of Variance; D000818:Animals; D016588:Anticarcinogenic Agents / Q000097:blood / Q000493:pharmacokinetics*; D001682:Biological Availability; D018938:Caco-2 Cells; D006801:Humans; D007211:Indoles / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D007275:Injections, Intravenous; D008297:Male; D008954:Models, Biological; D010539:Permeability; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility
chemical_list: D016588:Anticarcinogenic Agents; D007211:Indoles; C016392:3,3'-diindolylmethane