Characterisation of human tubular cell monolayers as a model of proximal tubular xenobiotic handling

Brown, Charles D.; Sayer, Rachel; Windass, Amy S.; Haslam, Iain S.; Broe, Marc E. De; D’Haese, Patrick C.; Verhulst, Anja

doi:10.1016/j.taap.2008.09.018

Cited by 141 publications

(115 citation statements)

References 31 publications

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“…Primary cultures have been described in other tissues, such as liver (LeCluyse, 2001) and kidney (Brown et al, 2008), as having a genetic profile similar to that of native tissue. However, primary human cells have high variability and short life spans, and availability is limited.…”

Section: Resultsmentioning

confidence: 99%

Gene Expression Profiling of Systems Involved in the Metabolism and the Disposition of Xenobiotics: Comparison between Human Intestinal Biopsy Samples and Colon Cell Lines

Bourgine¹,

Billaut-Laden²,

Happillon³

et al. 2012

Drug Metab Dispos

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ABSTRACT:Intestinal cell lines are used as in vitro models for pharmacological and toxicological studies. However, a general report of the gene expression spectrum of proteins that are involved in the metabolism and the disposition of xenobiotics in these in vitro systems is not currently available. To fill this information gap, we systematically characterized the expression profile of 377 genes encoding xenobiotic-metabolizing enzymes, transporters, and nuclear receptors and transcription factors in intestinal mucosa (ileum, ascending colon, transverse colon, descending colon, and rectum) from five healthy subjects and in five commonly used intestinal cell lines (Caco-2, C2BBe1, HT29, T84, and FHC).

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Section: Resultsmentioning

confidence: 99%

Gene Expression Profiling of Systems Involved in the Metabolism and the Disposition of Xenobiotics: Comparison between Human Intestinal Biopsy Samples and Colon Cell Lines

Bourgine¹,

Billaut-Laden²,

Happillon³

et al. 2012

Drug Metab Dispos

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“…a 1 mg/kg dose, b 100 mg/kg dose, and c 500 mg/kg dose. The color gradient ranges from blue (CL r equal to GFR × f u,p ) to red (maximal CL r indicated by the y-axis) achieved by determining the absolute or relative transporter expression through quantification of protein expression in cell lines and kidney samples; however, information regarding protein expression in rat and human kidney samples is lacking (26,27). In order to improve predictions, an understanding of the population variability in expression is necessary, requiring the quantitative analysis of a large pool of human kidney samples, with concurrent analysis of cell culture samples from which in vitro kinetic parameters have been generated.…”

Section: Discussionmentioning

confidence: 99%

Mechanistic Models Describing Active Renal Reabsorption and Secretion: A Simulation-Based Study

Felmlee

Dave

Morris

2012

AAPS J

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Abstract. The objective of the present study was to evaluate mechanistic pharmacokinetic models describing active renal secretion and reabsorption over a range of Michaelis-Menten parameter estimates and doses. Plasma concentration and urinary excretion profiles were simulated and renal clearance (CL r ) was calculated for two pharmacokinetic models describing active renal reabsorption (R1/ R2), two models describing active secretion (S1/S2), and a model containing both processes. A range of doses (1-1,000 mg/kg) was evaluated, and V max and K m parameter estimates were varied over a 100-fold range. Similar CL r values were predicted for reabsorption models (R1/R2) with variations in V max and K m . Tubular secretion models (S1/S2) yielded similar relationships between Michaelis-Menten parameter perturbations and CL r , but the predicted CL r values were threefold higher for model S1. For both reabsorption and secretion models, the greatest changes in CL r were observed with perturbations in V max , suggesting the need for an accurate estimate of this parameter. When intrinsic clearance was substituted for Michaelis-Menten parameters, it failed to predict similar CL r values even within the linear range. For models S1 and S2, renal secretion was predominant at low doses, whereas renal clearance was driven by fraction unbound in plasma at high doses. Simulations demonstrated the importance of Michaelis-Menten parameter estimates (especially V max ) for determining CL r . K m estimates can easily be obtained directly from in vitro studies. However, additional scaling of in vitro V max estimates using in vitro/in vivo extrapolation methods are required to incorporate these parameters into pharmacokinetic models.

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“…In addition, expression and function of several major drug transporters and enzymes are well maintained following a few days in culture, although reduced expression may be expected after longer culture times (13,35,36). Such in vitro models of proximal tubule drug transport enable a holistic understanding of the processes; for example, reduction in functional activity due to inhibition or knockdown of one or more transporters can be investigated.…”

Section: Primary Cultured Renal Tubule Cellsmentioning

confidence: 99%

Key to Opening Kidney for In Vitro–In Vivo Extrapolation Entrance in Health and Disease: Part I: In Vitro Systems and Physiological Data

Scotcher

Jones²,

Posada

et al. 2016

AAPS J

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ABSTRACT.The programme for the 2015 AAPS Annual Meeting and Exhibition (Orlando, FL; 25-29 October 2015) included a sunrise session presenting an overview of the state-of-the-art tools for in vitro-in vivo extrapolation (IVIVE) and mechanistic prediction of renal drug disposition. These concepts are based on approaches developed for prediction of hepatic clearance, with consideration of scaling factors physiologically relevant to kidney and the unique and complex structural organisation of this organ. Physiologically relevant kidney models require a number of parameters for mechanistic description of processes, supported by quantitative information on renal physiology (system parameters) and in vitro/in silico drug-related data. This review expands upon the themes raised during the session and highlights the importance of high quality in vitro drug data generated in appropriate experimental setup and robust system-related information for successful IVIVE of renal drug disposition. The different in vitro systems available for studying renal drug metabolism and transport are summarised and recent developments involving state-of-the-art technologies highlighted. Current gaps and uncertainties associated with system parameters related to human kidney for the development of physiologically based pharmacokinetic (PBPK) model and quantitative prediction of renal drug disposition, excretion, and/or metabolism are identified.

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Characterisation of human tubular cell monolayers as a model of proximal tubular xenobiotic handling

Cited by 141 publications

References 31 publications

Gene Expression Profiling of Systems Involved in the Metabolism and the Disposition of Xenobiotics: Comparison between Human Intestinal Biopsy Samples and Colon Cell Lines

Gene Expression Profiling of Systems Involved in the Metabolism and the Disposition of Xenobiotics: Comparison between Human Intestinal Biopsy Samples and Colon Cell Lines

Mechanistic Models Describing Active Renal Reabsorption and Secretion: A Simulation-Based Study

Key to Opening Kidney for In Vitro–In Vivo Extrapolation Entrance in Health and Disease: Part I: In Vitro Systems and Physiological Data

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