Exploring Kp,uu,BBB values smaller than unity in remoxipride: A physiologically-based CNS model approach highlighting brain metabolism in drugs with passive blood-brain barrier transport

European Journal of Pharmaceutical Sciences, vol. 203, pp. 106883

Abstract

(AIM): values < 1 are often interpreted as indicators of dominant active efflux transport processes at the blood-brain barrier (BBB). However, the potential impact of brain metabolism on this value is typically not addressed. In this study, we investigated the brain distribution of remoxipride, as a paradigm compound for passive BBB transport with yet unexplained brain elimination that was hypothesized to represent brain metabolism. (METHODS): ) rat microdialysis studies plasma and brainECF data were analysed. (RESULTS): The incorporation of active elimination through presumed brain metabolism of remoxipride in the LeiCNS-PK model significantly improved the prediction accuracy of experimentally observed brainECF profiles of this drug. The model integrated with brain metabolism in both barriers and organelles levels is named LeiCNS-PK3.5. (CONCLUSION): values < 1, not only the current interpretation of dominant BBB efflux transport, but also potential brain metabolism needs to be considered, especially because these may be concentration dependent. This will improve the mechanistic understanding of the processes that determine brain PK profiles.

Authors 4

1. Mengxu Zhang Aachen Division of Systems Pharmacology and Pharmacy Predictive Pharmacology group Leiden Academic Centre of Drug Research Gorlaeus Laboratories

   Leiden University

   Affiliation as printed

   Division of Systems Pharmacology and Pharmacy, Predictive Pharmacology Group, Leiden Academic Centre of Drug Research, Leiden University, Gorlaeus Laboratories, Leiden, the Netherlands

2. Ilona M. Vuist Aachen Charles River Laboratories

   Charles River Laboratories (Netherlands)

   Affiliation as printed

   Charles River Laboratories, Groningen, the Netherlands

3. Vivi Rottschäfer Aachen

   Leiden University · University of Amsterdam

   Affiliation as printed

   Mathematical Institute, Leiden University, Leiden, the Netherlands; Korteweg-de Vries Institute for Mathematics, University of Amsterdam, P.O. Box 94248, 1090 GE Amsterdam, the Netherlands

4. Elizabeth C. M. de Lange Aachen Division of Systems Pharmacology and Pharmacy Predictive Pharmacology group Leiden Academic Centre of Drug Research Gorlaeus Laboratories

   Leiden University

   Affiliation as printed

   Division of Systems Pharmacology and Pharmacy, Predictive Pharmacology Group, Leiden Academic Centre of Drug Research, Leiden University, Gorlaeus Laboratories, Leiden, the Netherlands. Electronic address: ecmdelange@lacdr.leidenuniv.nl