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Drug Metab Dispos. 2016 Mar;44(3):476-80. doi: 10.1124/dmd.115.067777. Epub 2016 Feb 3.

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.

Author information

1
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.) matthew.harwood@certara.com.
2
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.).

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.

PMID:
26842595
DOI:
10.1124/dmd.115.067777
[Indexed for MEDLINE]

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