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

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• 作者：Apurva R Patel^a ; Shawn D Spencer^a ; Mahavir B Chougule^a ; Stephen Safe^b ; ^c ; Mandip Singh^a ; ^{mandip.sachdeva@gmail.com}
• 关键词：DIM ; 3 ; 3&prime ; -diindolylmethane ; C-DIMs ; C-substituted diindolylmethanes ; IVIVC ; In Vitro&ndash ; In Vivo Correlation ; i.v. ; intravenous ; PPAR¦Ã ; peroxisome proliferator-activated receptor-¦Ã ; HBSS ; Hank&rsquo ; s balanced salt solution ; HEPES ; N-hydroxyethy
• 刊名：European Journal of Pharmaceutical Sciences
• 出版年：2012
• 出版时间：12 May, 2012
• 年：2012
• 卷：46
• 期：1-2
• 页码：8-16
• 全文大小：602 K

文摘

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 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 ¡À 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.