Absolute abundance and function of intestinal drug transporters: a prerequisite for fully mechanistic in vitro–in vivo extrapolation of oral drug absorption

MD Harwood, S. Neuhoff, G.L. Carlson, G. Warhurst, Amin Rostami-Hodjegan

Research output: Contribution to journalArticlepeer-review

375 Downloads (Pure)

Abstract

The use of whole body physiological-based pharmacokinetic (PBPK) models linked with in vitro-in vivo extrapolation (IVIVE) of kinetic parameters from laboratory experiments, has become embedded within many of the pharmaceutical industry and is used even as part of regulatory submissions. These include the influence of transporter proteins on drug disposition, a subject for which we have witnessed an increasing awareness. A combination of the development of high-powered analytical techniques and antibody-based technology, together with a realization that an understanding of absolute transporter protein abundances together with activity can potentially enhance the modelling of transporter kinetics by PBPK-IVIVE link models. This review summarizes the mechanistic approaches to integrate suitable non-biased in vitro transporter kinetic data relevant to the intestine (i.e. 'intrinsic' Ki, 'intrinsic' K m), by in vitro system modelling for these kinetic inputs with the advantages of, and challenges for, generating these data for input into PBPK models. This step is considered as a prerequisite for mechanistic modelling of the oral absorption for drugs that are substrates for transporters. Various approaches are provided to integrate intestinal transporter expression into PBPK models with a perspective on the incorporation of the absolute abundance/activity of transporters to enhance the predictive power of the models. We define the key intestinal tissue and functional expression-based scaling factors required. The objective is to use these for facilitating the extrapolation from in vitro intestinal transporter assays to the in vivo system, using absolute quantification methodologies. The models could be used to elucidate the complex relationship and relative importance of metabolizing enzymes and transporters in drug disposition and toxicity. Copyright © 2012 John Wiley & Sons, Ltd.
Original languageEnglish
Pages (from-to)2-28
Number of pages26
JournalBiopharm Drug Dispos
Volume34
Issue number1
Early online date7 Oct 2012
DOIs
Publication statusPublished - Jan 2013
EventDrug Transporter & Other Protein Quantification" Seminar featuring Professor Tetsuya Terasaki - Frankfurt Airport Hilton
Duration: 26 May 201426 May 2014

Keywords

  • absolute abundance
  • drug transporters
  • human intestine
  • ISEF-T
  • IVIVE
  • modelling and simulation
  • PBPK
  • transporter scaling

Fingerprint

Dive into the research topics of 'Absolute abundance and function of intestinal drug transporters: a prerequisite for fully mechanistic in vitro–in vivo extrapolation of oral drug absorption'. Together they form a unique fingerprint.

Cite this