Simulation-based assessment of the P-glycoprotein expression-activity relationship shows a drug and system dependency

Journal of Pharmacokinetics and Pharmacodynamics, vol. 53, pp. 10

Abstract

In vitro-in vivo extrapolation (IVIVE) of P-glycoprotein (P-gp) transporter activity bears two important assumptions: (1) P-gp expression (i.e., concentration) is linearly related to P-gp activity; and (2) this relation is drug independent. However, conflicting experimental results have been obtained about this relationship. This study therefore aimed to theoretically explore the P-gp expression-activity relationship (EAR). A P-gp membrane kinetic binding model was used to explore the P-gp EAR, and how this is impacted by different drugs as well as drug dose and initial P-gp expression. The model included passive permeability and drug interaction with P-gp described through the association (kon), dissociation (koff), and efflux rate (ke) constants. Simulations were first performed for 7 P-gp substrates, assuming an initial P-gp expression of 1000 µM and drug concentrations of 1 µM. Subsequently, the P-gp concentration was varied (2-300%) to derive the EAR. Next, to determine the impact of drug-specific and system-dependent properties on the P-gp EAR, virtual drugs varying in koff and ke were simulated, simultaneously considering different initial P-gp expressions and drug concentrations. Our simulations show that the P-gp EAR is not always linear, with the EAR showing both linear and non-linear behaviour depending on the drug. The koff/ke ratio of a drug was found to be an important determinant of the P-gp EAR, which shifted towards non-linearity for lower koff/ke ratios. Additionally, the P-gp EAR was more likely to be non-linear for higher ratios of the initial P-gp expression to drug concentration. In conclusion, this study shows that P-gp expression is not always proportional to P-gp activity, thereby explaining experimental contradictions about the EAR. This implies that using P-gp expression as single biomarker for P-gp activity needs to be reconsidered.

Authors 3

1. Daan W. van Valkengoed Aachen Division of Systems Pharmacology and Pharmacy Leiden Academic Centre for Drug Research

   Leiden University

   Affiliation as printed

   Division of Systems Pharmacology and Pharmacy, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands

2. Vivi Rottschäfer Aachen Mathematical Institute

   Leiden University · University of Amsterdam

   Affiliation as printed

   Korteweg-de Vries Institute for Mathematics, University of Amsterdam, Amsterdam, The Netherlands

   Mathematical Institute, Leiden University, Leiden, The Netherlands

3. Elizabeth C. M. de Lange corresponding Aachen Division of Systems Pharmacology and Pharmacy Leiden Academic Centre for Drug Research

   Leiden University

   Affiliation as printed

   Division of Systems Pharmacology and Pharmacy, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands. ecmdelange@lacdr.leidenuniv.nl