Precision-cut intestinal slices: alternative model for drug transport, metabolism, and toxicology research

ABSTRACT

Introduction: The absorption, distribution, metabolism, excretion and toxicity (ADME-tox) processes of drugs are of importance and require preclinical investigation intestine in addition to the liver. Various models have been developed for prediction of ADME-tox in the intestine. In this review, precision-cut intestinal slices (PCIS) are discussed and highlighted as model for ADME-tox studies.Areas covered: This review provides an overview of the applications and an update of the most recent research on PCIS as an ex vivo model to study the transport, metabolism and toxicology of drugs and other xenobiotics. The unique features of PCIS and the differences with other models as well as the translational aspects are also discussed.Expert opinion: PCIS are a simple, fast, and reliable ex vivo model for drug ADME-tox research. Therefore, PCIS are expected to become an indispensable link in the in vitro–ex vivo–in vivo extrapolation, and a bridge in translation of animal data to the human situation. In the future, this model may be helpful to study the effects of interorgan interactions, intestinal bacteria, excipients and drug formulations on the ADME-tox properties of drugs. The optimization of culture medium and the development of a (cryo)preservation technique require more research.

KEYWORDS:

• Drug–drug interaction
• drug metabolism
• drug transport
• ex vivo
• precision-cut intestinal slices
• toxicology

Article highlights

• After the introduction of tissue slicer and agarose filling and embedding, precision-cut intestinal slices (PCIS) has been established as ex vivo model for the intestine, which can be easily applied to the human intestine and that of various animals.

• As an alternative model, PCIS have an important potential for absorption, distribution, metabolism, excretion, and toxicity studies due to sufficient maintenance of tissue viability, activity and functionality to perform toxicity and induction studies, maintenance of cell polarity and cell–cell and cell–matrix contacts, relatively easy and fast preparation, efficient use of the scarce tissue resulting in 100–200 slices per experiment, applicability to the human situation, and convenience in studying regional and species differences, in compliance with replacement, reduction, and refinement. However, its limitations should also be taken into account.

• PCIS were applied to study drug transport related to efflux transporters (P-glycoprotein (P-gp), multidrug resistance-associated proteins) and influx transporters (apical sodium-dependent bile acid transporter). The ex vivo assessment of the transporters involved and the evaluation of the inhibitory potencies of their inhibitors are expected to make more accurate predictions for potential drug–drug interactions (DDIs) in vivo.

• Applications of PCIS on drug toxicity were focused on drug-induced gut injury by nonsteroidal anti-inflammatory drugs and toxic bile acids. PCIS are also promising in evaluating the toxicity of anticancer compounds.

• PCIS can be applied to predict DDIs by studying the induction and inhibition of drugs on the activity of drug transporters and drug metabolizing enzymes. Furthermore, the transport–metabolism interplay, for example, P-gp/CYP3A interplay, and interorgan interactions can be studied in PCIS.

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Declaration of interest

The work was funded by the China Scholarship Council (CSC) and the University of Groningen. The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.