The regulation of human hepatic drug transporter expression by activation of xenobiotic-sensing nuclear receptors

ABSTRACT

Introduction: If a drug is found to be an inducer of hepatic drug metabolizing enzymes via activation of nuclear receptors such as pregnane X receptor (PXR) or constitutive androstane receptor (CAR), it is likely that drug transporters regulated through these same receptors will be induced as well. This review highlights what is currently known about the molecular mechanisms that regulate transporter expression and where the research is directed.

Areas covered: This review is focused on publications that describe the role of activated hepatic nuclear receptors in the subsequent regulation of drug uptake and/or efflux transporters following exposure to xenobiotics.

Expert opinion: Many of the published studies on the role of nuclear receptors in the regulation of drug transporters involve non-human test animals. But due to species response differences, these associations are not always applicable to humans. For this reason, some relevant human in vitro models have been developed, such as primary or cryopreserved human hepatocytes, human liver slices, or HepG2 or HuH7 cell lines transiently or stably transfected with PXR expression and reporter constructs as well as in vivo models such as PXR-humanized mice. These human-relevant test systems will continue to be developed and applied for the testing of investigational drugs.

KEYWORDS:

• Drug transporters
• nuclear receptors
• human liver

Article highlights

• If a drug is an inducer of hepatic drug metabolizing enzymes via activation of nuclear receptors, it is likely that drug transporters regulated through these same receptors will be induced as well.

• Due to species differences in the induction or inhibition of these transporters, these drug effects may not always be apparent in conventional preclinical animal studies.

• Upregulation of drug transporters by CAR or PXR activators can accelerate the biotransformation of co-administered drugs, leading to decreased therapeutic efficacy, increased toxicity, or the increased bioactivation of prodrugs.

• Current drug interaction guidance documents place an increased emphasis on transporter-based DDI evaluations, involving both in vitro and in vivo studies of many different transporters.

• Relevant human in vitro models have been developed such as primary or cryopreserved human hepatocytes, human liver slices, liver chips, organoids, or HepG2 or HuH7 cell lines transiently or stably transfected with PXR expression and reporter constructs as well as in vivo models such as PXR- or CAR-humanized mice.

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Declaration of interest

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. This incluzdes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was not funded.