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

bioRxiv (Cold Spring Harbor Laboratory)

Abstract

Abstract (Aim) K p,uu,BBB values are crucial indicators of drug distribution into the brain, representing the steady-state relationship between unbound concentrations in plasma and in brain extracellular fluid (brainECF). K p,uu,BBB 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) The physiologically-based LeiCNS pharmacokinetic predictor (LeiCNS-PK model) was used to compare brain distribution of remoxipride with and without Michaelis-Menten kinetics at the BBB and/or brain cell organelle levels. To that end, multiple in-house (IV 0.7, 3.5, 4, 5.2, 7, 8, 14 and 16 mg/kg) and external (IV 4 and 8 mg/kg) 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) For drugs with K p,uu,BBB 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 Division of Systems Phrmcology nd Phrmcy Predictive Phrmcology group Leiden Acdemic Centre of Drug Reserch

   Leiden University

   Affiliation as printed

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

   Division of Systems Phrmcology nd Phrmcy, Predictive Phrmcology group, Leiden Acdemic Centre of Drug Reserch, Leiden University, Leiden, The Netherlnds

2. Ilona M. Vuist Aachen Charles River Laboratories

   Charles River Laboratories (Netherlands)

   Affiliation as printed

   Charles River Laboratories, Groningen, The Netherlands

   Charles River Laoratories, Groningen, The Netherlands

3. Vivi Rottschäfer Aachen Mathematical Institute Mathematial Institute

   Leiden University · University of Amsterdam

   Affiliation as printed

   Korteweg-de Vries Institute for Mathematics, University of Amsterdam, P.O. Box 94248, 1090 GE Amsterdam, The Netherlands

   Mathematical Institute, Leiden University, Leiden, The Netherlands

   Korteweg-e Vries Institute for Mathematics, University of Amsteram, P.O. Box 94248, 1090 GE Amsteram, The Netherlans

   Mathematial Institute, Leiden University, Leiden, The Netherlands

4. Elizabeth C. M. de Lange corresponding Aachen Division of Systems Pharmacology and Pharmacy Predictive Pharmacology group Leiden Academic Centre of Drug Research Division of Systems Phrmcology nd Phrmcy Predictive Phrmcology group Leiden Acdemic Centre of Drug Reserch

   Leiden University

   Affiliation as printed

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

   Division of Systems Phrmcology nd Phrmcy, Predictive Phrmcology group, Leiden Acdemic Centre of Drug Reserch, Leiden University, Leiden, The Netherlnds