Investigating ABCB1-mediated drug-drug interactions

Considerations for in vitro and in vivo assay design

Zsolt Sáfár, Balázs Vaskó, Tasha K. Ritchie, Gábor Imre, K. Mogyorósi, Franciska Erdo, Zsuzsanna Rajnai, Zsolt Fekete, Péter Szerémy, László Muka, Joseph K. Zolnerciks, Krisztina Herédi-Szabó, Isabelle Ragueneau-Majlessi, Péter Krajcsi

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Background: ABCB1 is a key ABC efflux transporter modulating the pharmacokinetics of a large percentage of drugs. ABCB1 is also a site of transporter mediated drug-drug interactions (tDDI). It is the transporter most frequently tested for tDDIs both in vitro and in the clinic. Objective: Understanding the limitations of various in vitro and in vivo models, therefore, is crucial. In this review we cover regulatory aspects of ABCB1 mediated drug transport as well as inhibition and the available models and methods. We also discuss protein structure and mechanistic aspects of transport as ABCB1 displays complex kinetics that involves multiple binding sites, potentiation of transport and probe-dependent IC50 values. Results: Permeability of drugs both passive and mediated by transporters is also a covariate that modulates apparent kinetic values. Levels of expression as well as lipid composition of the expression system used in in vitro studies have also been acknowledged as determinates of transporter activity. ABCB1-mediated clinical tDDIs are often complex as multiple transporters as well as metabolic enzymes may play a role. This complexity often masks the role of ABCB1 in tDDIs. Conclusion: It is expected that utilization of in vitro data will further increase with the refinement of simulations. It is also anticipated that transporter humanized preclinical models have a significant impact and utility.

Original languageEnglish
Pages (from-to)430-455
Number of pages26
JournalCurrent Drug Metabolism
Volume17
Issue number5
Publication statusPublished - Jun 1 2016

Fingerprint

Drug interactions
Drug Interactions
Assays
Pharmaceutical Preparations
Kinetics
Pharmacokinetics
ATP-Binding Cassette Transporters
Masks
Inhibitory Concentration 50
Permeability
Binding Sites
Lipids
In Vitro Techniques
Enzymes
Chemical analysis
Proteins

Keywords

  • Drug-drug interaction (DDI)
  • In vitro assay
  • In vivo assay
  • Membrane transporter
  • P-glycoprotein
  • Regulatory draft guidance

ASJC Scopus subject areas

  • Pharmacology
  • Clinical Biochemistry

Cite this

Sáfár, Z., Vaskó, B., Ritchie, T. K., Imre, G., Mogyorósi, K., Erdo, F., ... Krajcsi, P. (2016). Investigating ABCB1-mediated drug-drug interactions: Considerations for in vitro and in vivo assay design. Current Drug Metabolism, 17(5), 430-455.

Investigating ABCB1-mediated drug-drug interactions : Considerations for in vitro and in vivo assay design. / Sáfár, Zsolt; Vaskó, Balázs; Ritchie, Tasha K.; Imre, Gábor; Mogyorósi, K.; Erdo, Franciska; Rajnai, Zsuzsanna; Fekete, Zsolt; Szerémy, Péter; Muka, László; Zolnerciks, Joseph K.; Herédi-Szabó, Krisztina; Ragueneau-Majlessi, Isabelle; Krajcsi, Péter.

In: Current Drug Metabolism, Vol. 17, No. 5, 01.06.2016, p. 430-455.

Research output: Contribution to journalArticle

Sáfár, Z, Vaskó, B, Ritchie, TK, Imre, G, Mogyorósi, K, Erdo, F, Rajnai, Z, Fekete, Z, Szerémy, P, Muka, L, Zolnerciks, JK, Herédi-Szabó, K, Ragueneau-Majlessi, I & Krajcsi, P 2016, 'Investigating ABCB1-mediated drug-drug interactions: Considerations for in vitro and in vivo assay design', Current Drug Metabolism, vol. 17, no. 5, pp. 430-455.
Sáfár, Zsolt ; Vaskó, Balázs ; Ritchie, Tasha K. ; Imre, Gábor ; Mogyorósi, K. ; Erdo, Franciska ; Rajnai, Zsuzsanna ; Fekete, Zsolt ; Szerémy, Péter ; Muka, László ; Zolnerciks, Joseph K. ; Herédi-Szabó, Krisztina ; Ragueneau-Majlessi, Isabelle ; Krajcsi, Péter. / Investigating ABCB1-mediated drug-drug interactions : Considerations for in vitro and in vivo assay design. In: Current Drug Metabolism. 2016 ; Vol. 17, No. 5. pp. 430-455.
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