PT  - JOURNAL ARTICLE
AU  - Harwood, Matthew D.
AU  - Achour, Brahim
AU  - Neuhoff, Sibylle
AU  - Russell, Matthew R.
AU  - Carlson, Gordon
AU  - Warhurst, Geoffrey
AU  - Rostami-Hodjegan, Amin
TI  - 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
AID  - 10.1124/dmd.115.067777
DP  - 2016 Mar 01
TA  - Drug Metabolism and Disposition
PG  - 476--480
VI  - 44
IP  - 3
4099  - http://dmd.aspetjournals.org/content/44/3/476.short
4100  - http://dmd.aspetjournals.org/content/44/3/476.full
SO  - Drug Metab Dispos2016 Mar 01; 44
AB  - 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.