Opioids as Substrates and Inhibitors of the Genetically Highly Variable Organic Cation Transporter OCT1

Meyer, Marleen J.; Neumann, Viktoria E; Friesacher, Hannah Rosa; Zdrazil, Barbara; Brockmöller, Jürgen; Tzvetkov, Mladen V.

doi:10.1021/acs.jmedchem.9b01301

Cited by 25 publications

(24 citation statements)

References 49 publications

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“…Our results suggest that OCTs only contribute to a minor extent. Although MDMA is not a good OCT substrate, its metabolites might possibly be (as we had previously shown analogously for different opioids, where their more hydrophilic metabolites were better OCT substrates (Meyer et al, 2019)). For example, the main metabolites 3,4dihydroxyamphetamine and 3,4-dihydroxymethamphetamine are more hydrophilic than MDMA and might thus potentially be better OCT substrates, as they would likely rely more strongly on transport mechanisms to traverse cell membranes.…”

Section: Discussionmentioning

confidence: 66%

Cellular Uptake of Psychostimulants – Are High- and Low-Affinity Organic Cation Transporters Drug Traffickers?

et al. 2021

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Psychostimulants are used therapeutically and for illegal recreational purposes. Many of these are inhibitors of the presynaptic noradrenaline, dopamine, and serotonin transporters (NET, DAT, and SERT). According to their physicochemical properties, some might also be substrates of polyspecific organic cation transporters (OCTs) that mediate uptake in liver and kidneys for metabolism and excretion. OCT1 is genetically highly polymorphic, with strong effects on transporter activity and expression. To study potential interindividual differences in their pharmacokinetics, 18 psychostimulants and hallucinogens were assessed in vitro for transport by different OCTs as well as by the high-affinity monoamine transporters NET, DAT, and SERT. The hallucinogenic natural compound mescaline was found to be strongly transported by wild-type OCT1 with a Km of 24.3 µM and a vmax of 642 pmol × mg protein−1 × min−1. Transport was modestly reduced in variants *2 and *7, more strongly reduced in *3 and *4, and lowest in *5 and *6, while *8 showed a moderately increased transport capacity. The other phenylethylamine derivatives methamphetamine, para-methoxymethamphetamine, (-)-ephedrine, and cathine ((+)-norpseudoephedrine), as well as dimethyltryptamine, were substrates of OCT2 with Km values in the range of 7.9–46.0 µM and vmax values between 70.7 and 570 pmol × mg protein−1 × min−1. Affinities were similar or modestly reduced and the transport capacities were reduced down to half in the naturally occurring variant A270S. Cathine was found to be a substrate for NET and DAT, with the Km being 21-fold and the vmax 10-fold higher for DAT but still significantly lower compared to OCT2. This study has shown that several psychostimulants and hallucinogens are substrates for OCTs. Given the extensive cellular uptake of mescaline by the genetically highly polymorphic OCT1, strong interindividual variation in the pharmacokinetics of mescaline might be possible, which could be a reason for highly variable adverse reactions. The involvement of the polymorphic OCT2 in the renal excretion of several psychostimulants could be one reason for individual differences in toxicity.

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Section: Discussionmentioning

confidence: 66%

Cellular Uptake of Psychostimulants – Are High- and Low-Affinity Organic Cation Transporters Drug Traffickers?

et al. 2021

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“…Indeed, the published ligand-based pharmacophore models of OCT1 differ in the number, type, and distance of their features. While the models of Bednarczyk et al (2003), Moaddel et al (Moaddel et al, 2005;Moaddel et al, 2007) and from our group (Meyer et al, 2019) show some resemblance, the model by Nies et al (2011) shows more pronounced differences, the most striking being the absence of a positively ionizable site. This is not surprising and may simply reflect the coexistence of different binding sites in OCT1.…”

Section: Oct1 Polyspecificity As a Foementioning

confidence: 57%

OCT1 Polyspecificity—Friend or Foe?

Meyer

Tzvetkov

2021

Front. Pharmacol.

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“…In vitro studies that analyzed opioids as inhibitors of OCT1, Meyer et al showed that the calculated maximal unbound plasma concentrations for most of the tested opioids are lower than the obtained IC 50 values for OCT1 mediated transport (Meyer et al, 2019). Only the maximal portal vein concentration of tapentadol was comparable to the obtained IC 50 value, indicating a potential drug-drug interaction in vivo (Meyer et al, 2019). Furthermore, the influence of endogenous expression of transport proteins in the different cell lines, the use of different cell models (e.g., Table 1: K m TEA determined in MDCK cells, HEK293 cells and HeLa cells) and the independent establishment of several stable transfectants by different working groups lead to interlaboratory variability in the gained K m and IC 50 values and to a limited IVIVE.…”

Section: Discussionmentioning

confidence: 97%

“…Many drugs listed in Supplementary Table S2 only inhibit the transport of substrates at concentrations above their therapeutic plasma concentration or environmentally exposed concentration so that the inhibitory potential is more theoretically relevant (Chedik et al, 2019). In vitro studies that analyzed opioids as inhibitors of OCT1, Meyer et al showed that the calculated maximal unbound plasma concentrations for most of the tested opioids are lower than the obtained IC 50 values for OCT1 mediated transport (Meyer et al, 2019). Only the maximal portal vein concentration of tapentadol was comparable to the obtained IC 50 value, indicating a potential drug-drug interaction in vivo (Meyer et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

“…Recent publications emphasized the use of in silico predictions and machine learning approaches for the identification of new OCT1 substrates and their molecular characteristics (Baidya et al, 2020;Jensen et al, 2021). The OCT1 substrate and/or inhibitor spectrum has intensively been studied by various groups [e.g., (Gorboulev et al, 1997;Ciarimboli et al, 2005;Wenge et al, 2011;Tzvetkov et al, 2013;Knop et al, 2015;Otter et al, 2017;Meyer et al, 2019;Jensen et al, 2020b;Koepsell, 2020)]. Single-transfected cell models have also been extensively used to study the influence of genetic polymorphisms in the SLC22A1 gene on kinetic parameters of the OCT1-mediated transport (Kerb et al, 2002;Shu et al, 2003;Tzvetkov et al, 2011;Tzvetkov et al, 2013;Dos Santos Pereira et al, 2014;Matthaei et al, 2016;Meyer et al, 2017;Jensen et al, 2020b).…”

Section: Cell Models To Study Organic Cation Transporter 1 Transport Function Single-transfected Cell Models For Investigating Organic Camentioning

confidence: 99%

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Transport of Drugs and Endogenous Compounds Mediated by Human OCT1: Studies in Single- and Double-Transfected Cell Models

2021

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Organic Cation Transporter 1 (OCT1, gene symbol: SLC22A1) is predominately expressed in human liver, localized in the basolateral membrane of hepatocytes and facilitates the uptake of endogenous compounds (e.g. serotonin, acetylcholine, thiamine), and widely prescribed drugs (e.g. metformin, fenoterol, morphine). Furthermore, exogenous compounds such as MPP+, ASP+ and Tetraethylammonium can be used as prototypic substrates to study the OCT1-mediated transport in vitro. Single-transfected cell lines recombinantly overexpressing OCT1 (e.g., HEK-OCT1) were established to study OCT1-mediated uptake and to evaluate transporter-mediated drug-drug interactions in vitro. Furthermore, double-transfected cell models simultaneously overexpressing basolaterally localized OCT1 together with an apically localized export protein have been established. Most of these cell models are based on polarized grown MDCK cells and can be used to analyze transcellular transport, mimicking the transport processes e.g. during the hepatobiliary elimination of drugs. Multidrug and toxin extrusion protein 1 (MATE1, gene symbol: SLC47A1) and the ATP-driven efflux pump P-glycoprotein (P-gp, gene symbol: ABCB1) are both expressed in the canalicular membrane of human hepatocytes and are described as transporters of organic cations. OCT1 and MATE1 have an overlapping substrate spectrum, indicating an important interplay of both transport proteins during the hepatobiliary elimination of drugs. Due to the important role of OCT1 for the transport of endogenous compounds and drugs, in vitro cell systems are important for the determination of the substrate spectrum of OCT1, the understanding of the molecular mechanisms of polarized transport, and the investigation of potential drug-drug interactions. Therefore, the aim of this review article is to summarize the current knowledge on cell systems recombinantly overexpressing human OCT1.

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Opioids as Substrates and Inhibitors of the Genetically Highly Variable Organic Cation Transporter OCT1

Cited by 25 publications

References 49 publications

Cellular Uptake of Psychostimulants – Are High- and Low-Affinity Organic Cation Transporters Drug Traffickers?

Cellular Uptake of Psychostimulants – Are High- and Low-Affinity Organic Cation Transporters Drug Traffickers?

OCT1 Polyspecificity—Friend or Foe?

Transport of Drugs and Endogenous Compounds Mediated by Human OCT1: Studies in Single- and Double-Transfected Cell Models

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