Pharmacokinetic evaluation and in vitro-in vivo correlation (IVIVC) of novel methylene-substituted 3,3' diindolylmethane (DIM).
Pharmacokinetic evaluation and in vitro-in vivo correlation (IVIVC) of novel methylene-substituted 3,3' diindolylmethane (DIM).
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DOI：
10.1016/j.ejps.2012.01.012
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发表时间：
2012-05-12
影响因子：
4.6
通讯作者：
Singh, Mandip
中科院分区：
文献类型：
--
作者：
Patel, Apurva R.;Spencer, Shawn D.;Chougule, Mahavir B.;Safe, Stephen;Singh, Mandip
3，3 ′-二吲哚基甲烷（DIM）是十字花科蔬菜中吲哚-3-甲醇酸催化低聚反应的主要产物。1，1-二（3′-吲哚基）-1-（对位取代苯基）甲烷[C-substituted diindolylmethanes，C-DIMs]是一类新的由吲哚-3-甲醇衍生的抗癌化合物。尽管关于DIM-C-pPhC 6 H5的化学预防性质的机制的知识迅速增加，但确定DIM-C-pPhC 6 H5的吸收和药代动力学性质以探索其临床效用的研究相对较少。在这项研究中，我们评估了亚甲基取代的DIM的溶解度、亲脂性和Caco-2细胞渗透性。在大鼠中，在静脉注射和口服DIM的新型类似物后测定药代动力学特性。使用WinNonlin® 5.0软件，使用非房室和房室技术测定药代动力学参数。为了探索体外渗透性值与口服吸收药代动力学之间的潜在体外-体内相关性（IVIVC），我们使用三室精确Loo-Riegelman方法对静脉注射和口服数据进行了去卷积。在生理学相关剂量下，采用微分方程，通过三房室模型结合零级/Michaelis-Menten有限全身吸收描述经口吸收和处置。获得的饱和模型解释了Cmax/剂量的非线性变化，绝对生物利用度（0.13 ± 0.06）也具有剂量依赖性。DIMC-pPhC 6 H5在Caco-2细胞中的吸收速率曲线与体内显著不同。结论：提出的药代动力学吸收模型代表了获得生物利用度差，高亲脂性药物，如DIM类似物DIM-C-pPhC 6 H5的血浆水平可预测性的有用基础。
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. 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. 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.
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影响因子：
5.7
作者：
Lei, Ping;Abdelrahim, Maen;Safe, Stephen
通讯作者：
Safe, Stephen
影响因子：
120.1
作者：
Leeson, Paul D.;Springthorpe, Brian
通讯作者：
Springthorpe, Brian
影响因子：
3.7
作者：
Chen, Xiaoxi;Murawski, Anthony;Balimane, Praveen V.
通讯作者：
Balimane, Praveen V.
影响因子：
3.7
作者：
Polli, JE;Ginski, MJ
通讯作者：
Ginski, MJ
DOI：
10.1016/0006-291x(91)91647-u
发表时间：
1991-03-29
影响因子：
3.1
作者：
ARTURSSON, P;KARLSSON, J
通讯作者：
KARLSSON, J