Pharmacokinetic evaluation and In Vitro–In Vivo Correlation (IVIVC) of novel methylene-substituted 3,3′ diindolylmethane (DIM)

Abstract

Purpose 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 noncompartmental 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 Cmax/Dose, and the absolute bioavailability (0.13 ± 0.06) was also dose dependent. The absorption rate profile of DIMC-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.

Evaluation of Spray BIO-Max DIM-P in Dogs for Oral Bioavailability and in Nu/nu Mice Bearing Orthotopic/Metastatic Lung Tumor Models for Anticancer Activity

“…Response surface designs was used to discover variables that offers process and product improvement in the experimental region using polynomial equation (2). The objective was to select the formulation composition for SB DIM-P which could improve bioavailability significantly compared to that of free drug.…”

“…Our laboratory has reported the promising anticancer activity of 1, 1-bis (3′-indolyl)-1-(p-substituted phenyl) methanes (DIM-P) [C-substituted di-indole-methane derivative (DIMs)] (2) in lung cancer models by inhalation and oral routes of administration (3,4). DIM-P in combination with docetaxel showed moderate synergistic anticancer activity in lung tumor cell lines in vitro and additive effect in vivo.…”

“…DIM-P in combination with docetaxel showed moderate synergistic anticancer activity in lung tumor cell lines in vitro and additive effect in vivo. Further, even though DIM-P is a desirable anticancer agent, its activity as a single agent is limited due to its poor oral bioavailability which is only 13% (2). …”

EphA2 Targeting Pegylated Nanocarrier Drug Delivery System for Treatment of Lung Cancer

“…Animals were randomly distributed into experimental groups ( n = 6) and fasted overnight prior to experiment. Blood samples (250 µL) were collected by heart puncture at the following time points: 0, 0.017, 0.25, 0.5, 0.75, 1, 3, 6, 8, 12 and 24 h. Samples were processed and extracted drug was analyzed by HPLC analysis (36). Briefly, DIM-P was separated from plasma by protein precipitation using acetonitrile and samples were centrifuged for 15 min at 10,000 g. Sample was run on a mobile phase consisting of acetonitrile and water (90:10% v/v) using a Waters Symmetry® C18 guard column (5 µm, 3.9×20 mm) and a Waters Symmetry® C18 column (5 µm, 4.6 × 250 mm) at a flow rate of 1.0 mL/min and DIM-P was monitored at 242 nm.…”

In vitro–in vivocorrelations: general concepts, methodologies and regulatory applications

“…As a model-independent approach, deconvolution have gained popularity in the last years because it refuses the assumption of model-dependency, allowing more flexibility 2,3,9,10,11,[14][15][16][17]38,55,56,96,97,103,104,[119][120][121][122][123][124][125][126][127][128] (see Table 7). However, the use of averaged data in some articles is still controversial and it has become itself an important research field.…”