Title
Towards human ex vivo organ perfusion models to elucidate drug pharmacokinetics in health and disease
Author
Stevens, L.J.
Donkers, J.M.
Dubbel, J.
Vaes, W.H.J.
van de Steeg, E.
Knibbe, C.A.J.
Alwayn, I.P.J.
van de Steeg, E.
Publication year
2020
Abstract
To predict the absorption, distribution, metabolism and excretion (ADME) profile of candidate drugs a variety of preclinical models can be applied. The ADME and toxicological behavior of newly developed drugs are often investigated prior to assessment in humans, which is associated with long time-lines and high costs. Therefore, good predictions of ADME profiles earlier in the drug development process are very valuable. Good prediction of intestinal absorption and renal and biliary excretion remain especially difficult, as there is an interplay of active transport and metabolism involved. To study these processes, including enterohepatic circulation, ex vivo tissue models are highly relevant and can be regarded as the bridge between in vitro and in vivo models. In this review the current in vitro, in vivo and in more detail ex vivo models for studying pharmacokinetics in health and disease are discussed. Additionally, we propose novel models, i.e., perfused whole-organs, which we envision will generate valuable pharmacokinetic information in the future due to improved translation to the in vivo situation. These machine-perfused organ models will be particularly interesting in combination with biomarkers for assessing the functionality of transporter and CYP450 proteins.
Subject
Preclinical models
Biliary and renal secretion
Drug-drug interactions
Endogenous biomarkers
Perfusion models
Pharmacokinetics
Biological marker
Cytochrome P450
Compartment model
Enteropathy
Ex vivo study
Health status
Human
In vitro study
In vivo study
Intestine perfusion
Kidney disease
liver perfusion
Organ perfusion
Pharmacokinetic parameters
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http://resolver.tudelft.nl/uuid:9cf1bb8e-8760-449f-95ec-9bf867d12faf
DOI
https://doi.org/10.1080/03602532.2020.1772280
TNO identifier
952580
Source
Drug Metabolism Reviews, 52 (52), 438-454
Document type
article