Organic Anion Transporter 3 Interacts Selectively with Lipophilic<i>β</i>-Lactam Antibiotics

Wolman, Aaron T.; Gionfriddo, Michael R.; Heindel, Gregory A; Mukhija, Paran; Witkowski, Sarah; Bommareddy, Ajay; VanWert, Adam L.

doi:10.1124/dmd.112.049569

Cited by 37 publications

(24 citation statements)

References 32 publications

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“…Such an approach was therefore explored in this project/programme for renal uptake and clearance since such a relationship would afford rapid optimization of ligand-transporter interactions. Interestingly, since the completion of this study, a recent publication supports the notion that lipophilic inhibitors of OAT may also be substrates (Wolman et al, 2013).…”

Section: Discussionsupporting

confidence: 66%

Application of anin vitroOAT assay in drug design and optimization of renal clearance

et al. 2014

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1. Optimization of renal clearance is a complex balance between passive and active processes mediated by renal transporters. This work aimed to characterize the interaction of a series of compounds with rat and human organic anion transporters (OATs) and develop quantitative structure-activity relationships (QSARs) to optimize renal clearance. 2. In vitro inhibition assays were established for human OAT1 and rat Oat3 and rat in vivo renal clearance was obtained. Statistically significant quantitative relationships were explored between the compounds' physical properties, their affinity for OAT1 and oat3 and the inter-relationship with unbound renal clearance (URC) in rat. 3. Many of the compounds were actively secreted and in vitro analysis demonstrated that these were ligands for rat and human OAT transporters (IC50 values ranging from <1 to >100 µM). Application of resultant QSAR models reduced renal clearance in the rat from 24 to <0.1 ml/min/kg. Data analysis indicated that the properties associated with increasing affinity at OATs are the same as those associated with reducing URC but orthogonal in nature. 4. This study has demonstrated that OAT inhibition data and QSAR models can be successfully used to optimize rat renal clearance in vivo and provide confidence of translation to humans.

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Section: Discussionsupporting

confidence: 66%

Application of anin vitroOAT assay in drug design and optimization of renal clearance

et al. 2014

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“…Previously, studies in our group and others have demonstrated the potential of efflux transporter inhibition at the BBB to increase brain levels of neuropsychopharmacological agents [36,37]. OAT3 can be inhibited by probenecid, penicillins and statins [31,38,39]. Even though probenecid inhibits all members of the Oat family, it was chosen for use in this study as it is a more potent inhibitor of oat3 than oat1/oat2,[40] and oat3 is the only member of this transporter family which has been found to be functionally important at the BBB [29,33].…”

Section: Introductionmentioning

confidence: 99%

“…[29,30] OAT3 is an efflux transporter involved in effluxing anions, such as bumetanide, from the blood into renal tubule cells, and from the brain via the BBB. [24,27,28,[30][31][32][33] Oat3 is the only member of the Oat family to be found in BCEC or the brain to a quantifiable extent. [27,29,30] It has been reported that substrate specificity does not differ much between human and rat forms of oat3.…”

Section: Introductionmentioning

confidence: 99%

“…[36,37] OAT3 can be inhibited by probenecid, penicillins and statins. [31,38,39] Even though probenecid inhibits all members of the Oat family, it was chosen for use in this study as it is a more potent inhibitor of oat3 than oat1/oat2, [40] and oat3 is the only member of this transporter family which has been found to be functionally important at the BBB. [29,33] In addition, probenecid was used due to its previous success as an adjunctive agent used to enhance systemic levels of penicillins, its previous demonstrated use as an oat3-mediated efflux inhibitor at the BBB and its established clinical safety.…”

Section: Introductionmentioning

confidence: 99%

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The effect of organic anion transporter 3 inhibitor probenecid on bumetanide levels in the brain: an integrated in vivo microdialysis study in the rat

Donovan

O’Brien

Boylan

et al. 2015

Journal of Pharmacy and Pharmacology

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“…To generate an OAT1-centered interaction network, this broad list of metabolites was then filtered and ranked by their potential to interact with OAT1. QSAR and pharmacophore modeling have been used to analyze limited sets of OAT drugs/substrates (6,9,18,38,39). Although many drugs appear to be related to metabolites and signaling molecules (40,41), the availability of chemical libraries and computational tools have led to more systematic comparisons of metabolites, natural compounds, and drugs (42)(43)(44)(45).…”

Section: Resultsmentioning

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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Organic Anion Transporter 3 Interacts Selectively with Lipophilicβ-Lactam Antibiotics

Cited by 37 publications

References 32 publications

Application of anin vitroOAT assay in drug design and optimization of renal clearance

Application of anin vitroOAT assay in drug design and optimization of renal clearance

The effect of organic anion transporter 3 inhibitor probenecid on bumetanide levels in the brain: an integrated in vivo microdialysis study in the rat

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

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