Developmental regulation of kidney and liver solute carrier and ATP-binding cassette drug transporters and drug metabolizing enzymes: the role of remote organ communication

ABSTRACT

Introduction: The ontogeny of drug transport and metabolism is generally studied independently in tissues, yet in the immediate postnatal period the developmental regulation of SLC and ABC transporters and metabolizing enzymes must be coordinated. Using the Remote Sensing and Signaling Hypothesis as a framework, we describe how a systems physiology view helps to make sense of how inter-organ communication via hepatic, renal, and intestinal transporters and drug metabolizing enzymes (DMEs) is regulated from the immediate postnatal period through adulthood.

Areas covered: This review examines patterns of developmental expression and function of transporters and DMEs with a focus on how cross-talk between these proteins in the kidney, liver and other organs (e.g., intestine) may be coordinated postnatally to optimize levels of metabolites and endogenous signaling molecules as well as gut-microbiome products.

Expert opinion/commentary: Developmental expression is considered in terms of the Remote Sensing and Signaling Hypothesis, which addresses how transporters and DMEs participate in inter-organ and inter-organism small molecule communication in health, development, and disease. This hypothesis, for which there is growing support, is particularly relevant to the ‘birth transition’ and post-natal developmental physiology when organs must deal with critical physiological tasks distinct from the fetal period and where remote inter-organ and possibly inter-organismal (e.g. infant-gut microbiome) communication is likely to be critical to maintain homeostasis.

KEYWORDS:

• Drug metabolism
• transport
• ontogeny
• development

Article highlights

• The transition between the late prenatal and immediate postnatal periods is one of the most profound in terms of gene expression as well as physiology. A systems physiology view, using the Remote Sensing and Signaling Hypothesis as a framework, seeks to understand how the intestine, liver, and kidney SLC and ABC transporters and drug metabolizing enzymes (DMEs) are regulated from the immediate postnatal period through adulthood.

• The developmental regulation of renal and hepatic drug transporters and DMEs must be coordinated to optimize for different sets of small molecules that are important in postnatal physiology.

• A deeper understanding of changes over developmental time in gene and protein expression (including function and regulation), organ and systemic metabolism, and classical organ physiology—both in the context of individual organs and multiple ‘remotely communicating’ organs—is critical for more appropriate pharmaceutical treatment of neonates and young children.

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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 includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

This work was funded in part by grants from the National Institutes of Health (NIH) (U54HD090259 & DK109392) awarded to S Nigam