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Research ArticleArticle

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

Matthew D. Harwood, Brahim Achour, Sibylle Neuhoff, Matthew R. Russell, Gordon Carlson, Geoffrey Warhurst and Amin Rostami-Hodjegan
Drug Metabolism and Disposition March 2016, 44 (3) 476-480; DOI: https://doi.org/10.1124/dmd.115.067777
Matthew D. Harwood
Gut Barrier Group, Inflammation and Repair, University of Manchester, Salford Royal NHS Trust, Salford, United Kingdom (M.D.H., G.C., G.W.); Simcyp Limited (a Certara company), Blades Enterprise Centre, Sheffield, United Kingdom (M.D.H., S.N., A.R.-H.); and Centre for Applied Pharmacokinetic Research, Manchester Pharmacy School, Stopford Building, Manchester, United Kingdom (B.A., M.R.R., A.R.-H.)
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Brahim Achour
Gut Barrier Group, Inflammation and Repair, University of Manchester, Salford Royal NHS Trust, Salford, United Kingdom (M.D.H., G.C., G.W.); Simcyp Limited (a Certara company), Blades Enterprise Centre, Sheffield, United Kingdom (M.D.H., S.N., A.R.-H.); and Centre for Applied Pharmacokinetic Research, Manchester Pharmacy School, Stopford Building, Manchester, United Kingdom (B.A., M.R.R., A.R.-H.)
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Sibylle Neuhoff
Gut Barrier Group, Inflammation and Repair, University of Manchester, Salford Royal NHS Trust, Salford, United Kingdom (M.D.H., G.C., G.W.); Simcyp Limited (a Certara company), Blades Enterprise Centre, Sheffield, United Kingdom (M.D.H., S.N., A.R.-H.); and Centre for Applied Pharmacokinetic Research, Manchester Pharmacy School, Stopford Building, Manchester, United Kingdom (B.A., M.R.R., A.R.-H.)
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Matthew R. Russell
Gut Barrier Group, Inflammation and Repair, University of Manchester, Salford Royal NHS Trust, Salford, United Kingdom (M.D.H., G.C., G.W.); Simcyp Limited (a Certara company), Blades Enterprise Centre, Sheffield, United Kingdom (M.D.H., S.N., A.R.-H.); and Centre for Applied Pharmacokinetic Research, Manchester Pharmacy School, Stopford Building, Manchester, United Kingdom (B.A., M.R.R., A.R.-H.)
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Gordon Carlson
Gut Barrier Group, Inflammation and Repair, University of Manchester, Salford Royal NHS Trust, Salford, United Kingdom (M.D.H., G.C., G.W.); Simcyp Limited (a Certara company), Blades Enterprise Centre, Sheffield, United Kingdom (M.D.H., S.N., A.R.-H.); and Centre for Applied Pharmacokinetic Research, Manchester Pharmacy School, Stopford Building, Manchester, United Kingdom (B.A., M.R.R., A.R.-H.)
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Geoffrey Warhurst
Gut Barrier Group, Inflammation and Repair, University of Manchester, Salford Royal NHS Trust, Salford, United Kingdom (M.D.H., G.C., G.W.); Simcyp Limited (a Certara company), Blades Enterprise Centre, Sheffield, United Kingdom (M.D.H., S.N., A.R.-H.); and Centre for Applied Pharmacokinetic Research, Manchester Pharmacy School, Stopford Building, Manchester, United Kingdom (B.A., M.R.R., A.R.-H.)
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Amin Rostami-Hodjegan
Gut Barrier Group, Inflammation and Repair, University of Manchester, Salford Royal NHS Trust, Salford, United Kingdom (M.D.H., G.C., G.W.); Simcyp Limited (a Certara company), Blades Enterprise Centre, Sheffield, United Kingdom (M.D.H., S.N., A.R.-H.); and Centre for Applied Pharmacokinetic Research, Manchester Pharmacy School, Stopford Building, Manchester, United Kingdom (B.A., M.R.R., A.R.-H.)
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Abstract

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), generated from the same samples and using different proteomic methodologies from independent laboratories, on PBPK outcomes was assessed. A 5-fold decrease in REFiP-gp for a single oral dose of digoxin resulted in a 1.19- and 1.31-fold higher plasma area under the curve and Cmax, respectively. All generated REFiP-gp values led to simulated digoxin Cmax values within observed ranges; however, combining kinetic data generated from a different laboratory with the 5-fold lower REFiP-gp could not recover a digoxin-rifampicin drug-drug interaction, emphasizing the necessity to obtain transporter-specific kinetic estimates and REFs from the same in vitro system. For a theoretical BCRP compound, with absorption taking place primarily in the jejunum, a decrease in the REFiBCRP from 2.22 (University of Manchester) to 1.11 (Bertin Pharma) promoted proximal intestinal absorption while delaying tmax 1.44-fold. Laboratory-specific differences in REF may lead to different IVIVE-PBPK outcomes. To understand the mechanisms underlying projected pharmacokinetic liabilities, it is important to assess the potential impact of bias on the generation of REFs on an interindividual basis within a target population.

Footnotes

    • Received October 9, 2015.
    • Accepted February 1, 2016.
  • dx.doi.org/10.1124/dmd.115.067777.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 44 (3)
Drug Metabolism and Disposition
Vol. 44, Issue 3
1 Mar 2016
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Research ArticleArticle

Impact of Cross-Laboratory Differences of Intestinal REF on IVIVE-PBPK

Matthew D. Harwood, Brahim Achour, Sibylle Neuhoff, Matthew R. Russell, Gordon Carlson, Geoffrey Warhurst and Amin Rostami-Hodjegan
Drug Metabolism and Disposition March 1, 2016, 44 (3) 476-480; DOI: https://doi.org/10.1124/dmd.115.067777

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Research ArticleArticle

Impact of Cross-Laboratory Differences of Intestinal REF on IVIVE-PBPK

Matthew D. Harwood, Brahim Achour, Sibylle Neuhoff, Matthew R. Russell, Gordon Carlson, Geoffrey Warhurst and Amin Rostami-Hodjegan
Drug Metabolism and Disposition March 1, 2016, 44 (3) 476-480; DOI: https://doi.org/10.1124/dmd.115.067777
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