Clinical Application of Pharmacokinetic and Pharmacodynamic Models

Billard, V.

doi:10.1007/978-1-4419-9192-8_6

Cited by 2 publications

(2 citation statements)

References 43 publications

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“…As an example, pharmacokinetic models are routinely used to guide drug dosing and predict elimination in various clinical situations. 10,11 A representative pharmacokinetic model is depicted in figure 1 where drug is administered in a depot compartment and diffuses following concentration gradients to a central and a peripheral compartment. A d (t) represents the amount of drug in the depot compartment, A c (t) the amount of drug in the central compartment and A p (t) the amount of drug in the peripheral compartment.…”

Section: How To Model Systems With Spatial Structurementioning

confidence: 99%

Equation-based models of dynamic biological systems

Daun

Rubin

Vodovotz

et al. 2008

Journal of Critical Care

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The purpose of this review is to introduce differential equations as a simulation tool in the biological and clinical sciences. This modeling technique is very mature and has been a preferred tool of physiologists and bioengineers and of quantitative scientists in general to describe and predict the behavior of complex interacting systems. However, this methodology has not been widely used within clinical medicine due to a lack of familiarity with highly quantitative methods and a greater acquaintance with statistical modeling approaches based on inference and empirical data analysis. We will describe various aspects of equation-based modeling, including underlying assumptions, strengths, and weaknesses and provide specific examples of simple models. We conclude that the usefulness of quantitative modeling, including equation-based models, is ultimately linked to the quality and abundance of observation obtained on the system being modeled. Equation-based modeling, although potentially an integrative approach, is complementary to and extends the potential of traditional statistically based approaches to inference.

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Section: How To Model Systems With Spatial Structurementioning

confidence: 99%

Equation-based models of dynamic biological systems

Daun

Rubin

Vodovotz

et al. 2008

Journal of Critical Care

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“…Active transport such as efflux moves compounds against chemical and concentration gradients, thus reducing intracellular concentrations or absorption of chemicals. Therapeutic agents, so-called intended chemicals, are also eliminated through transport and metabolism, and the elimination rate is directly related to their therapeutic effectiveness (Krishna and Mayer, 2000;Billard, 2003;Jansen et al, 2003). In addition, transport and metabolism are the most common sources for drug-drug interactions when two or more drugs are administered simultaneously.…”

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confidence: 99%

Simultaneous Substitution of Phenylalanine-305 and Aspartate-318 of Rat Pregnane X Receptor with the Corresponding Human Residues Abolishes the Ability to Transactivate the CYP3A23 Promoter

Song

Liu

et al. 2004

J Pharmacol Exp Ther

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The pregnane X receptor (PXR) is a key regulator on the expression of genes involved in the elimination of chemicals. As one of the most divergent members in the nuclear receptor family, PXR is activated in a highly species-dependent manner by certain chemicals. Pregnenolone 16␣-carbonitrile (PCN), a glucocorticoid antagonist, efficaciously activates rodent but not human PXR. This study was undertaken to investigate the structural basis for PCN-mediated activation of rat PXR. A series of rat-human chimeric PXRs were prepared to gradually replace the ligand-binding domain of human PXR with the corresponding rat sequence at an increasing length of 20 residues. Cotransfection experiments established that region 306 -326 acted as a transitional conjunction from none to full PCN responsive status. Site-directed mutagenesis study identified two residues (Phe-305 and Asp-318) that were critical in supporting PCN-mediated activation, and simultaneous substitution of both residues abolished the ability of rat PXR to transactivate the CYP3A23 promoter. In addition, substitutions on Phe-305, Asp-318, or both markedly reduced the basal transcriptional activity, and the reduction occurred with the CYP3A4 but not CYP3A23 promoter. Further study with CYP3A4 and CYP3A23 hybrid reporters demonstrated that the region harboring the distal PXR element in the CYP3A4 promoter mediated the repressive activity. PXR has been shown to interact with corepressors in the absence of ligand. The decreased responsiveness toward PCN and reduced basal transcriptional activity suggest that Phe-305 and Asp-318 are involved in both ligand-binding and corepressor interactions.

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Clinical Application of Pharmacokinetic and Pharmacodynamic Models

Cited by 2 publications

References 43 publications

Equation-based models of dynamic biological systems

Equation-based models of dynamic biological systems

Simultaneous Substitution of Phenylalanine-305 and Aspartate-318 of Rat Pregnane X Receptor with the Corresponding Human Residues Abolishes the Ability to Transactivate the CYP3A23 Promoter

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