Molecular Properties of Drugs Interacting with SLC22 Transporters OAT1, OAT3, OCT1, and OCT2: A Machine-Learning Approach

Liu, Henry C.; Goldenberg, Anne; Chen, Yu‐Chen; Lun, Christina; Wu, Wei; Bush, Kevin T.; Balac, Natasha; Rodriguez, Paul; Abagyan, Ruben; Nigám, Sanjay K.

doi:10.1124/jpet.116.232660

Cited by 68 publications

(56 citation statements)

References 46 publications

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“…The OCT family as a whole, including OCT2, also has a very broad substrate selectivity76, although few compounds have been reported to show the nanomolar affinity that we observed for p -tyramine. Both d-amphetamine and MDMA (3,4-methylenedioxymethamphetamine) are reported to show a greater affinity for OCT2 than other family members42 and both are also high affinity ligands for TAAR14.…”

Section: Discussionmentioning

confidence: 68%

Pharmacological characterization of a high-affinity p-tyramine transporter in rat brain synaptosomes

Berry

Hart

Pryor

et al. 2016

Sci Rep

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p-Tyramine is an archetypal member of the endogenous family of monoamines known as trace amines, and is one of the endogenous agonists for trace amine-associated receptor (TAAR)1. While much work has focused on the function of TAAR1, very little is known about the regulation of the endogenous agonists. We have previously reported that p-tyramine readily crosses lipid bilayers and that its release from synaptosomes is non-exocytotic. Such release, however, showed characteristics of modification by one or more transporters. Here we provide the first characterization of such a transporter. Using frontal cortical and striatal synaptosomes we show that p-tyramine passage across synaptosome membranes is not modified by selective inhibition of either the dopamine, noradrenaline or 5-HT transporters. In contrast, inhibition of uptake-2 transporters significantly slowed p-tyramine re-uptake. Using inhibitors of varying selectivity, we identify Organic Cation Transporter 2 (OCT2; SLC22A2) as mediating high affinity uptake of p-tyramine at physiologically relevant concentrations. Further, we confirm the presence of OCT2 protein in synaptosomes. These results provide the first identification of a high affinity neuronal transporter for p-tyramine, and also confirm the recently described localization of OCT2 in pre-synaptic terminals.

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Section: Discussionmentioning

confidence: 68%

Pharmacological characterization of a high-affinity p-tyramine transporter in rat brain synaptosomes

Berry

Hart

Pryor

et al. 2016

Sci Rep

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“…Subsequent studies have shown that OAT1 and the closely related OAT3 (SLC22A8) transport organic anions (e.g., nonsteroidal anti‐inflammatory drugs, and urate) as well as organic cations (e.g., cimetidine) and organic zwitterions (e.g., carnitine). Nevertheless, both OATs have, as implied by their names, a strong preference for organic anions; this is further borne out by recent machine‐learning analyses of molecular features of substrates interacting with OAT1, OAT3, OCT1, and OCT2 24 …”

Section: Oat1 and Other Oats As Exemplary Slc “Drug” And Metabolite Tmentioning

confidence: 99%

The Systems Biology of Drug Metabolizing Enzymes and Transporters: Relevance to Quantitative Systems Pharmacology

Nigám

Bush

Bhatnagar

et al. 2020

Clin Pharma and Therapeutics

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Quantitative systems pharmacology (QSP) has emerged as a transformative science in drug discovery and development. It is now time to fully rethink the biological functions of drug metabolizing enzymes (DMEs) and transporters within the framework of QSP models. The large set of DME and transporter genes are generally considered from the perspective of the absorption, distribution, metabolism, and excretion (ADME) of drugs. However, there is a growing amount of data on the endogenous physiology of DMEs and transporters. Recent studies—including systems biology analyses of “omics” data as well as metabolomics studies—indicate that these enzymes and transporters, which are often among the most highly expressed genes in tissues like liver, kidney, and intestine, have coordinated roles in fundamental biological processes. Multispecific DMEs and transporters work together with oligospecific and monospecific ADME proteins in a large multiorgan remote sensing and signaling network. We use the Remote Sensing and Signaling Theory (RSST) to examine the roles of DMEs and transporters in intratissue, interorgan, and interorganismal communication via metabolites and signaling molecules. This RSST‐based view is applicable to bile acids, uric acid, eicosanoids, fatty acids, uremic toxins, and gut microbiome products, among other small organic molecules of physiological interest. Rooting this broader perspective of DMEs and transporters within QSP may facilitate an improved understanding of fundamental biology, physiologically based pharmacokinetics, and the prediction of drug toxicities based upon the interplay of these ADME proteins with key pathways in metabolism and signaling. The RSST‐based view should also enable more tailored pharmacotherapy in the setting of kidney disease, liver disease, metabolic syndrome, and diabetes. We further discuss the pharmaceutical and regulatory implications of this revised view through the lens of systems physiology.

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“…is generally assessed by monitoring the uptake of a single, presumably representative, substrate. Interestingly, the pharmacophores generated by different groups to describe the molecular determinants of ligand interaction with OCT2, although qualitatively similar in their inclusion of several common structural characteristics (including hydrophobicity, hydrogen-bonding features, and positive charge), differ from one another with respect to the three-dimensional placement of these elements (Suhre et al, 2005;Zolk et al, 2009;Nies et al, 2011a;Xu et al, 2013;Liu et al, 2016). This led to the suggestion that ligand interaction with OCT2 may be influenced by the choice of substrate used to assess transport activity (Belzer et al, 2013), an idea supported by the observation that IC 50 values for the inhibition of OCT2 activity produced by six commonly prescribed drugs were, on average, 9-to 10-fold greater when using MPP as a substrate than when using metformin as a substrate (Zolk et al, 2009;Belzer et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Assessment of Substrate-Dependent Ligand Interactions at the Organic Cation Transporter OCT2 Using Six Model Substrates

et al. 2018

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Organic cation transporter (OCT) 2 mediates the entry step for organic cation secretion by renal proximal tubule cells and is a site of unwanted drug-drug interactions (DDIs). But reliance on decision tree-based predictions of DDIs at OCT2 that depend on IC values can be suspect because they can be influenced by choice of transported substrate; for example, IC values for the inhibition of metformin versus MPP transport can vary by 5- to 10-fold. However, it is not clear whether the substrate dependence of a ligand interaction is common among OCT2 substrates. To address this question, we screened the inhibitory effectiveness of 20 M concentrations of several hundred compounds against OCT2-mediated uptake of six structurally distinct substrates: MPP, metformin,,,-trimethyl-2-[methyl(7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino]ethanaminium (NBD-MTMA), TEA, cimetidine, and 4-4-dimethylaminostyryl--methylpyridinium (ASP). Of these, MPP transport was least sensitive to inhibition. IC values for 20 structurally diverse compounds confirmed this profile, with IC values for MPP averaging 6-fold larger than those for the other substrates. Bayesian machine-learning models of ligand-induced inhibition displayed generally good statistics after cross-validation and external testing. Applying our ASP model to a previously published large-scale screening study for inhibition of OCT2-mediated ASP transport resulted in comparable statistics, with approximately 75% of "active" inhibitors predicted correctly. The differential sensitivity of MPP transport to inhibition suggests that multiple ligands can interact simultaneously with OCT2 and supports the recommendation that MPP not be used as a test substrate for OCT2 screening. Instead, metformin appears to be a comparatively representative OCT2 substrate for both in vitro and in vivo (clinical) use.

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Molecular Properties of Drugs Interacting with SLC22 Transporters OAT1, OAT3, OCT1, and OCT2: A Machine-Learning Approach

Cited by 68 publications

References 46 publications

Pharmacological characterization of a high-affinity p-tyramine transporter in rat brain synaptosomes

Pharmacological characterization of a high-affinity p-tyramine transporter in rat brain synaptosomes

The Systems Biology of Drug Metabolizing Enzymes and Transporters: Relevance to Quantitative Systems Pharmacology

Assessment of Substrate-Dependent Ligand Interactions at the Organic Cation Transporter OCT2 Using Six Model Substrates

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