Regulatory Science Perspectives on Transporter Studies in Drug Development

Lee, Sue‐Chih; Zhang, Lei; Huang, Shiew‐Mei

doi:10.1002/9781118705308.ch23

Cited by 2 publications

(2 citation statements)

References 65 publications

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“…There are now US Food and Drug Administration (FDA) regulatory guidelines to examine the transport of new drugs with a view toward understanding DDIs at the transporter level (27). Indeed, the FDA recommends that applications for new drugs and biologics in which renal secretion is significant be studied in vitro to determine whether these agents are substrates for OAT1, OAT3, or OCT2 (28).…”

Section: Drugs and Toxinsmentioning

confidence: 99%

Handling of Drugs, Metabolites, and Uremic Toxins by Kidney Proximal Tubule Drug Transporters

Nigám¹,

Wu²,

Bush³

et al. 2015

Clinical Journal of the American Society of Nephrology

227

192

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The proximal tubule of the kidney plays a crucial role in the renal handling of drugs (e.g., diuretics), uremic toxins (e.g., indoxyl sulfate), environmental toxins (e.g., mercury, aristolochic acid), metabolites (e.g., uric acid), dietary compounds, and signaling molecules. This process is dependent on many multispecific transporters of the solute carrier (SLC) superfamily, including organic anion transporter (OAT) and organic cation transporter (OCT) subfamilies, and the ATP-binding cassette (ABC) superfamily. We review the basic physiology of these SLC and ABC transporters, many of which are often called drug transporters. With an emphasis on OAT1 (SLC22A6), the closely related OAT3 (SLC22A8), and OCT2 (SLC22A2), we explore the implications of recent in vitro, in vivo, and clinical data pertinent to the kidney. The analysis of murine knockouts has revealed a key role for these transporters in the renal handling not only of drugs and toxins but also of gut microbiome products, as well as liverderived phase 1 and phase 2 metabolites, including putative uremic toxins (among other molecules of metabolic and clinical importance). Functional activity of these transporters (and polymorphisms affecting it) plays a key role in drug handling and nephrotoxicity. These transporters may also play a role in remote sensing and signaling, as part of a versatile small molecule communication network operative throughout the body in normal and diseased states, such as AKI and CKD.

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Section: Drugs and Toxinsmentioning

confidence: 99%

Handling of Drugs, Metabolites, and Uremic Toxins by Kidney Proximal Tubule Drug Transporters

Nigám¹,

Wu²,

Bush³

et al. 2015

Clinical Journal of the American Society of Nephrology

227

192

View full text Add to dashboard Cite

show abstract

“…The OAT1 drug transporter is a focus of regulatory agencies concerned about side effects of drugs due to interaction at the level of the transporter (55,56). For some time, it has been clear that OAT1 and other drug transporters play key roles in regulating levels of endogenous metabolites and signaling molecules (11,21,27,57).…”

Section: Discussionmentioning

confidence: 99%

An Organic Anion Transporter 1 (OAT1)-centered Metabolic Network

Liu

Jamshidi

Chen³

et al. 2016

Journal of Biological Chemistry

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There has been a recent interest in the broader physiological importance of multispecific "drug" transporters of the SLC and ABC transporter families. Here, a novel multi-tiered systems biology approach was used to predict metabolites and signaling molecules potentially affected by the in vivo deletion of organic anion transporter 1 (Oat1, Slc22a6, originally NKT), a major kidney-expressed drug transporter. Validation of some predictions in wetlab assays, together with re-evaluation of existing transport and knock-out metabolomics data, generated an experimentally validated, confidence ranked set of OAT1-interacting endogenous compounds enabling construction of an "OAT1-centered metabolic interaction network." Pathway and enrichment analysis indicated an important role for OAT1 in metabolism involving: the TCA cycle, tryptophan and other amino acids, fatty acids, prostaglandins, cyclic nucleotides, odorants, polyamines, and vitamins. The partly validated reconstructed network is also consistent with a major role for OAT1 in modulating metabolic and signaling pathways involving uric acid, gut microbiome products, and socalled uremic toxins accumulating in chronic kidney disease. Together, the findings are compatible with the hypothesized role of drug transporters in remote inter-organ and inter-organismal communication: The Remote Sensing and Signaling Hypothesis (Nigam, S. K. (2015) Nat. Rev. Drug Disc. 14, 29). The fact that OAT1 can affect many systemic biological pathways suggests that drug-metabolite interactions need to be considered beyond simple competition for the drug transporter itself and may explain aspects of drug-induced metabolic syndrome. Our approach should provide novel mechanistic insights into the role of OAT1 and other drug transporters implicated in metabolic diseases like gout, diabetes, and chronic kidney disease.A great deal of recent evidence suggests that solute carriers (SLC) 2 play a much broader role in physiology, including signaling and metabolism, than has been previously appreciated (1, 2). Indeed, there has been a recent call for more systematic analysis of the roles of SLCs in metabolism and signaling (1). Perhaps due to heavy emphasis on their key role in pharmacokinetics, members of the SLC (and ABC as well) "drug" transporter families are not generally depicted in biochemical pathways involving the endogenous metabolites they transport (2). Such an omission could have clinical consequences, because drugs directly or indirectly affect pathways normally involved in the movement of key metabolites, pathway intermediates, and signaling molecules, thereby fundamentally affecting cell and organ physiology in normal, pathophysiological, and developmental situations (1, 2). According to the remote sensing and signaling hypothesis, SLC and ABC drug transporters are important in regulating the movement of small endogenous molecules such as key metabolites (e.g. ␣-ketoglutarate, tryptophan metabolites), signaling molecules (e.g. cAMP, prostaglandins, polyamines), vitamins, antioxidant...

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Regulatory Science Perspectives on Transporter Studies in Drug Development

Cited by 2 publications

References 65 publications

Handling of Drugs, Metabolites, and Uremic Toxins by Kidney Proximal Tubule Drug Transporters

Handling of Drugs, Metabolites, and Uremic Toxins by Kidney Proximal Tubule Drug Transporters

An Organic Anion Transporter 1 (OAT1)-centered Metabolic Network

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