Quantitative in vitro to in vivo extrapolation of tissues toxicity

Hamon, Jérémy; Renner, Maria; Jamei, Masoud; Lukas, Arno; Kopp‐Schneider, Annette; Bois, Frédéric

doi:10.1016/j.tiv.2015.01.011

Cited by 29 publications

(22 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…), but also as a critical step in the interpretation of safety‐related issues in animals and their extrapolation to humans (Hamon et al . ). The development of PBPK models for psychoactive drugs (and other drugs that can penetrate the BBB), particularly when they are subject to active uptake or efflux, is therefore dependent on robust and reliable measurement of the abundances of BBB transporters in humans as well as animal species used in pre‐clinical studies (Ball et al .…”

Section: Discussionmentioning

confidence: 97%

“…The quantification of BBB transporters is important not only in pharmacokinetic studies to understand the disposition of drugs and their metabolites into the CNS and to elucidate drug-drug interactions (Giacomini et al 2010;Kalvass et al 2013), but also as a critical step in the interpretation of safety-related issues in animals and their extrapolation to humans (Hamon et al 2015). The development of PBPK models for psychoactive drugs (and other drugs that can penetrate the BBB), particularly when they are subject to active uptake or efflux, is therefore dependent on robust and reliable measurement of the abundances of BBB transporters in humans as well as animal species used in pre-clinical studies (Ball et al 2014;Gaohua et al 2016).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Identification and quantification of blood–brain barrier transporters in isolated rat brain microvessels

Feteisi

Al‐Majdoub

Achour

et al. 2018

Journal of Neurochemistry

View full text Add to dashboard Cite

The blood-brain barrier (BBB) maintains brain homeostasis by tightly regulating the exchange of molecules with systemic circulation. It consists primarily of microvascular endothelial cells surrounded by astrocytic endfeet, pericytes, and microglia. Understanding the make-up of transporters in rat BBB is essential to the translation of pharmacological and toxicological observations into humans. In this study, experimental workflows are presented in which the optimization of (a) isolation of rat brain microvessels (b) enrichment of endothelial cells, and (c) extraction and digestion of proteins were evaluated, followed by identification and quantification of BBB proteins. Optimization of microvessel isolation was indicated by 15-fold enrichment of endothelial cell marker Glut1 mRNA, whereas markers for other cell types were not enriched. Filter-aided sample preparation was shown to be superior to in-solution sample preparation (10251 peptides vs. 7533 peptides). Label-free proteomics was used to identify nearly 2000 proteins and quantify 1276 proteins in isolated microvessels. A combination of targeted and global proteomics was adopted to measure protein abundance of 6 ATP-binding cassette and 27 solute carrier transporters. Data analysis using proprietary Progenesis and open access MaxQuant software showed overall agreement; however, Abcb9 and Slc22a8 were quantified only by MaxQuant, whereas Abcc9 and Abcd3 were quantified only by Progenesis. Agreement between targeted and untargeted quantification was demonstrated for Abcb1 (19.7 ± 1.4 vs. 17.8 ± 2.3) and Abcc4 (2.2 ± 0.7 vs. 2.1 ± 0.4), respectively. Rigorous quantification of BBB proteins, as reported in this study, should assist with translational modeling efforts involving brain disposition of xenobiotics.

show abstract

Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Identification and quantification of blood–brain barrier transporters in isolated rat brain microvessels

Feteisi

Al‐Majdoub

Achour

et al. 2018

Journal of Neurochemistry

View full text Add to dashboard Cite

show abstract

“…PBPK modeling allows the prediction of the time course of a compound's concentration in blood and target tissues. It also has the potential to address repeated dose toxicity testing (Pfaller et al, 2015;Hamon et al, 2015;Kramer et al, 2015). Information from other models, such as those predicting metabolite formation, are increasingly included in PBPK models, rendering results that are more predictive (Lock et al, 2012).…”

Section: In Vitro Pharmacokineticsmentioning

confidence: 99%

“…Forsby and Blaauboer, 2007), acute oral toxicity and repeated dose toxicity (Gubbels-van Hal et al, 2005), developmental toxicity (Louisse et al, 2010;Verwei et al, 2006) and genotoxicity (Paini et al, 2010). Within the framework of the European integrated project Predict-IV (Pfaller et al, 2015) work was devoted to pharmacokinetic modeling of in vitro experiments, physiologically based pharmacokinetic (PBPK) modeling, mechanistic models of toxicity for the kidney and brain, large scale dose-response analysis methods, and biomarker discovery tools (Hamon et al, 2015). The value of this emphasis on biokinetics for evaluating the toxicity of compounds after repeated exposure of cellular systems in vitro was clearly shown in this project (Kramer et al, 2015;Wilmes et al, 2013).…”

Section: Quantitative In Vitro To In Vivo Extrapolation (Qivive)mentioning

confidence: 99%

Evidence-based absorption, distribution, metabolism, excretion (ADME) and its interplay with alternative toxicity methods

Tsaioun

Blaauboer

Hartung

2016

ALTEX

View full text Add to dashboard Cite

“…The advantages of this approach have been discussed in general terms in previous publications (93,94), and relevance to renal drug toxicity and renal DDIs are highlighted in the sections above and below. However, validating such models can be challenging due to lack of suitable clinical data.…”

Section: Utility and Challenges In Predicting Intracellular Concentramentioning

confidence: 99%

Key to Opening Kidney for In Vitro-In Vivo Extrapolation Entrance in Health and Disease: Part II: Mechanistic Models and In Vitro-In Vivo Extrapolation

Scotcher

Jones²,

Posada

et al. 2016

AAPS J

View full text Add to dashboard Cite

Abstract.It is envisaged that application of mechanistic models will improve prediction of changes in renal disposition due to drug-drug interactions, genetic polymorphism in enzymes and transporters and/or renal impairment. However, developing and validating mechanistic kidney models is challenging due to the number of processes that may occur (filtration, secretion, reabsorption and metabolism) in this complex organ. Prediction of human renal drug disposition from preclinical species may be hampered by species differences in the expression and activity of drug metabolising enzymes and transporters. A proposed solution is bottom-up prediction of pharmacokinetic parameters based on in vitro-in vivo extrapolation (IVIVE), mediated by recent advances in in vitro experimental techniques and application of relevant scaling factors. This review is a follow-up to the Part I of the report from the 2015 AAPS Annual Meeting and Exhibition (Orlando, FL; 25th-29th October 2015) which focuses on IVIVE and mechanistic prediction of renal drug disposition. It describes the various mechanistic kidney models that may be used to investigate renal drug disposition. Particular attention is given to efforts that have attempted to incorporate elements of IVIVE. In addition, the use of mechanistic models in prediction of renal drugdrug interactions and potential for application in determining suitable adjustment of dose in kidney disease are discussed. The need for suitable clinical pharmacokinetics data for the purposes of delineating mechanistic aspects of kidney models in various scenarios is highlighted.KEY WORDS: active renal excretion; human kidney transporters; human renal drug clearance; kidney disease; non-hepatic drug metabolism.

show abstract

Quantitative in vitro to in vivo extrapolation of tissues toxicity

Cited by 29 publications

References 39 publications

Identification and quantification of blood–brain barrier transporters in isolated rat brain microvessels

Identification and quantification of blood–brain barrier transporters in isolated rat brain microvessels

Evidence-based absorption, distribution, metabolism, excretion (ADME) and its interplay with alternative toxicity methods

Key to Opening Kidney for In Vitro-In Vivo Extrapolation Entrance in Health and Disease: Part II: Mechanistic Models and In Vitro-In Vivo Extrapolation

Contact Info

Product

Resources

About