Predicting Passive and Active Tissue:Plasma Partition Coefficients: Interindividual and Interspecies Variability

Ruark, Christopher D.; Hack, C. Eric; Robinson, Peter; Mahle, Deirdre A.; Gearhart, Jeffery M.

doi:10.1002/jps.24011

Cited by 41 publications

(58 citation statements)

References 30 publications

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“…K t:pl values in tissues of rat were calculated according to the method previously described (Ruark et al, 2014). A high K t:pl was obtained in adipose tissue, indicating that DPT possessed high affinity to adipose tissue.…”

Section: Resultsmentioning

confidence: 99%

“…Several in silico methods to estimate K t:pl have been reported (Poulin and Theil, 2002; Berezhkovskiy, 2004; Rodgers and Rowland, 2006; Schmitt, 2008; Peyret et al, 2010; Ruark et al, 2014). In the present study, K t:pl values in rat were calculated using the approach developed recently by Ruark et al (2014), which was considered to provide a more comprehensive tissue composition model than previous approaches.…”

Section: Discussionmentioning

confidence: 99%

“…In the present study, K t:pl values in rat were calculated using the approach developed recently by Ruark et al (2014), which was considered to provide a more comprehensive tissue composition model than previous approaches. In a previous attempt we employed K t:pl values of rat throughout the models, resulting in poor predictions in the other three animals, which might be due to large interspecies difference in unbound fraction of DPT in plasma (from 5.39% in rat to 0.16% in dog).…”

Section: Discussionmentioning

confidence: 99%

“…K t:pl of DPT in rat were estimated according to a method previously described based on tissue composition of rat (Ruark et al, 2014). Ionization, lipophilicity and the fraction unbound in plasma of compound were incorporated into the calculation.…”

Section: Methodsmentioning

confidence: 99%

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Prediction of Deoxypodophyllotoxin Disposition in Mouse, Rat, Monkey, and Dog by Physiologically Based Pharmacokinetic Model and the Extrapolation to Human

et al. 2016

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Deoxypodophyllotoxin (DPT) is a potential anti-tumor candidate prior to its clinical phase. The aim of the study was to develop a physiologically based pharmacokinetic (PBPK) model consisting of 13 tissue compartments to predict DPT disposition in mouse, rat, monkey, and dog based on in vitro and in silico inputs. Since large interspecies difference was found in unbound fraction of DPT in plasma, we assumed that Kt:pl,u (unbound tissue-to-plasma concentration ratio) was identical across species. The predictions of our model were then validated by in vivo data of corresponding preclinical species, along with visual predictive checks. Reasonable matches were found between observed and predicted plasma concentrations and pharmacokinetic parameters in all four animal species. The prediction in the related seven tissues of mouse was also desirable. We also attempted to predict human pharmacokinetic profile by both the developed PBPK model and interspecies allometric scaling across mouse, rat and monkey, while dog was excluded from the scaling. The two approaches reached similar results. We hope the study will help in the efficacy and safety assessment of DPT in future clinical studies and provide a reference to the preclinical screening of similar compounds by PBPK model.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Prediction of Deoxypodophyllotoxin Disposition in Mouse, Rat, Monkey, and Dog by Physiologically Based Pharmacokinetic Model and the Extrapolation to Human

et al. 2016

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“…The tissue data needed for calculating partition coefficients in human and rat, taken from Ruark et al (2014), include: cellular and water fractions of total volume, lipid and protein fractions of cellular volume, lipid fractions of the total lipid volume, the pH of each tissue, and the fractional volume of protein in plasma. A default plasma pH of 7.4 is taken from Schmitt (2008b) in calculating ionization.…”

Section: Methodsmentioning

confidence: 99%

httk: R Package for High-Throughput Toxicokinetics

Pearce¹,

Setzer²,

Strope³

et al. 2017

J. Stat. Soft.

240

247

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Thousands of chemicals have been profiled by high-throughput screening programs such as ToxCast and Tox21; these chemicals are tested in part because most of them have limited or no data on hazard, exposure, or toxicokinetics. Toxicokinetic models aid in predicting tissue concentrations resulting from chemical exposure, and a “reverse dosimetry” approach can be used to predict exposure doses sufficient to cause tissue concentrations that have been identified as bioactive by high-throughput screening. We have created four toxicokinetic models within the R software package httk. These models are designed to be parameterized using high-throughput in vitro data (plasma protein binding and hepatic clearance), as well as structure-derived physicochemical properties and species-specific physiological data. The package contains tools for Monte Carlo sampling and reverse dosimetry along with functions for the analysis of concentration vs. time simulations. The package can currently use human in vitro data to make predictions for 553 chemicals in humans, rats, mice, dogs, and rabbits, including 94 pharmaceuticals and 415 ToxCast chemicals. For 67 of these chemicals, the package includes rat-specific in vitro data. This package is structured to be augmented with additional chemical data as they become available. Package httk enables the inclusion of toxicokinetics in the statistical analysis of chemicals undergoing high-throughput screening.

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The Need for Human Exposure Projection in the Interpretation of PreclinicalIn VitroandIn VivoADME Tox Data

Poulin

2016

Drug Discovery Toxicology

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Predicting Passive and Active Tissue:Plasma Partition Coefficients: Interindividual and Interspecies Variability

Cited by 41 publications

References 30 publications

Prediction of Deoxypodophyllotoxin Disposition in Mouse, Rat, Monkey, and Dog by Physiologically Based Pharmacokinetic Model and the Extrapolation to Human

Prediction of Deoxypodophyllotoxin Disposition in Mouse, Rat, Monkey, and Dog by Physiologically Based Pharmacokinetic Model and the Extrapolation to Human

httk: R Package for High-Throughput Toxicokinetics

The Need for Human Exposure Projection in the Interpretation of PreclinicalIn VitroandIn VivoADME Tox Data

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