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Authors: Matthew Harwood

Beam Me Up, Scotty! Probing the Mechanisms of Transporter-mediated Drug Disposition

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on Jul 27, 2018 8:00:08 AM
Matthew Harwood

Over the last 15 years, the importance of drug transporters has become paramount for understanding drug absorption, distribution into tissues, and in particular, drug-drug interactions (DDIs). In vitro-in vivo extrapolation (IVIVE) is an approach to link in vitro systems to the human in vivo situation using algorithms and physiologically-based scaling factors. In this blog, I […]

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Topics: PBPK Modeling & Simulation

Abundance of Hepatic Transporters in Caucasians: A Meta-analysis

The aim of this study was to derive quantitative abundance values for key hepatic transporters suitable for in vitro-in vivo extrapolation (IVIVE) within a physiologically-based pharmacokinetic modeling framework. A meta-analysis was performed whereby abundance measurements, sample preparation method and donor demography were collated from literature. In order to define values for a healthy Caucasian population, […]

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Breast Cancer Resistance Protein Abundance, but Not mRNA Expression, Correlates with Estron e-3-Sulfate Transport in Caco-2

Transporter mRNA and protein expression data are used to extrapolate in vitro transporter kinetics to in vivo drug disposition predictions. Breast cancer resistance protein (BCRP) possesses broad substrate specificity; therefore, understanding BCRP expression-activity relationships are necessary for the translation to in vivo. Bidirectional transport of estrone-3-sulfate (E-3-S), a BCRP probe, was evaluated with respect to relative BCRP mRNA expression […]

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The Next Horizons in Predicting Drug-drug Interactions

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on Mar 23, 2016 1:08:47 PM
Matthew Harwood

Physiologically-based pharmacokinetic (PBPK) modeling has arrived in prime time. This quantitative mechanistic framework, combining physiology with drug information and clinical trial design, has become an integral part of drug discovery and development. PBPK has also gained currency within industry and regulatory agencies. Its applications are numerous, including simulation of pre-clinical, healthy volunteer and special population […]

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Topics: PBPK Modeling & Simulation

In Vitro-In Vivo Extrapolation Scaling Factors for Intestinal P-glycoprotein and Breast Cancer Resistance Protein: Part I—A Cross-laboratory Comparison of Transporter-protein Abundances and Relative Expression Factors in Human Intestine and Caco-2 Cells

Over the last 5 years the quantification of transporter-protein absolute abundances has dramatically increased in parallel to the expanded use of in vitro-in vivo extrapolation (IVIVE) and physiologically based pharmacokinetics (PBPK)-linked models, for decision-making in pharmaceutical company drug development pipelines and regulatory submissions. Although several research groups have developed laboratory-specific proteomic workflows, it is unclear if the large range of reported variability is founded […]

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In Vitro-In Vivo Extrapolation Scaling Factors for Intestinal P-glycoprotein and Breast Cancer Resistance Protein: Part II—The Impact of Cross-laboratory Variations of Intestinal Transporter Relative Expression Factors on Predicted Drug Disposition

Relative expression factors (REFs) are used to scale in vitro transporter kinetic data via in vitro-in vivo extrapolation linked to physiologically based pharmacokinetic (IVIVE-PBPK) models to clinical observations. Primarily two techniques to quantify transporter protein expression are available, immunoblotting and liquid chromatography-tandem mass spectrometry. Literature-collated REFs ranged from 0.4 to 5.1 and 1.1 to 90 for intestinal P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), respectively. The impact of using human jejunum-Caco-2 REFs for P-gp (REFiP-gp) and BCRP (REFiBCRP), […]

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Application of an LC-MS/MS Method for the Simultaneous Quantification of Human Intestinal Transporter Proteins Absolute Abundance Using a QconCAT Technique

Transporter proteins expressed in the gastrointestinal tract play a major role in the oral absorption of some drugs, and their involvement may lead to drug-drug interaction (DDI) susceptibility when given in combination with drugs known to inhibit gut wall transporters. Anticipating such liabilities and predicting the magnitude of the impact of transporter proteins on oral drug absorption and DDIs requires quantification of […]

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