Substrates and Inhibitors of the Organic Cation Transporter 3 and Comparison with OCT1 and OCT2

Gebauer, Lukas; Jensen, Ole Nørregaard; Brockmöller, Jürgen; Dücker, Christof

doi:10.1021/acs.jmedchem.2c01075

Cited by 14 publications

(11 citation statements)

References 42 publications

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“…The investigated inhibitors included known OCT substrates such as salbutamol, sparteine, and zolmitriptan as well as substances previously identified as not-transported inhibitors like tolterodine and verapamil. 15 Except for ibuprofen, all substances were positively charged at physiological pH and had at least one chiral center.…”

Section: ■ Resultsmentioning

confidence: 99%

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Stereoselective Inhibition of High- and Low-Affinity Organic Cation Transporters

Gebauer,

Jensen,

Rafehi

et al. 2023

Mol. Pharmaceutics

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Many drugs have chiral centers and are therapeutically applied as racemates. Thus, the stereoselectivity in their interactions with membrane transporters needs to be addressed. Here, we studied stereoselectivity in inhibiting organic cation transporters (OCTs) 1, 2, and 3 and the high-affinity monoamine transporters (MATs) NET and SERT. Selectivity by the inhibition of 35 pairs of enantiomers significantly varied among the three closely related OCTs. OCT1 inhibition was nonselective in almost all cases, whereas OCT2 was stereoselectively inhibited by 45% of the analyzed drugs. However, the stereoselectivity of the OCT2 was only moderate with the highest selectivity observed for pramipexole. The (R)-enantiomer inhibited OCT2 4-fold more than the (S)-enantiomer. OCT3 showed the greatest stereoselectivity in its inhibition. (R)-Tolterodine and (S)-zolmitriptan inhibited OCT3 11-fold and 25-fold more than their respective counterparts. Interestingly, in most cases, the pharmacodynamically active enantiomer was also the stronger OCT inhibitor. In addition, stereoselectivity in the OCT inhibition appeared not to depend on the transported substrate. For high-affinity MATs, our data confirmed the stereoselective inhibition of NET and SERT by several antidepressants. However, the stereoselectivity measured here was generally lower than that reported in the literature. Unexpectedly, the high-affinity MATs were not significantly more stereoselectively inhibited than the polyspecific OCTs. Combining our in vitro OCT inhibition data with available stereoselective pharmacokinetic analyses revealed different risks of drug–drug interactions, especially at OCT2. For the tricyclic antidepressant doxepine, only the (E)-isomer showed an increased risk of drug–drug interactions according to guidelines from regulatory authorities for renal transporters. However, most chiral drugs show only minor stereoselectivity in the inhibition of OCTs in vitro, which is unlikely to translate into clinical consequences.

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Section: ■ Resultsmentioning

confidence: 99%

“…13 All three mediate the cellular uptake of numerous drugs but also of endogenous and environmental compounds. 14,15 OCT inhibition has been studied in detail. Data for several hundred inhibitors of OCT1, 2, and 3 have been published.…”

Section: ■ Introductionmentioning

confidence: 99%

Stereoselective Inhibition of High- and Low-Affinity Organic Cation Transporters

Gebauer,

Jensen,

Rafehi

et al. 2023

Mol. Pharmaceutics

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“…The orange filling of each box indicates the respective proportions of chiral drugs. These OCT substrates were identified earlier. − Overview of substrates investigated in this study (B). Chiral centers are highlighted with asterisks.…”

Section: Introductionmentioning

confidence: 85%

“…OCTs transport hydrophilic, mainly (but not exclusively) positively charged substances with low to moderate molecular weight between 150 and 450 Da. − Drugs of different therapeutic areas are transported by OCTs. Most prominent are drugs acting as β-adrenergic receptor agonists or muscarinic acetylcholine receptor antagonists (Figure A).…”

Section: Introductionmentioning

confidence: 99%

Stereoselectivity in Cell Uptake by SLC22 Organic Cation Transporters 1, 2, and 3

Gebauer,

Jensen,

Rafehi

et al. 2023

J. Med. Chem.

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Stereoselectivity can be most relevant in drug metabolism and receptor binding. Although drug membrane transport might be equally important for small-molecule pharmacokinetics, the extent of stereoselectivity in membrane transport is largely unknown. Here, we characterized the stereoselective transport of 18 substrates of SLC22 organic cation transporters (OCTs) 1, 2, and 3. OCT2 and OCT3 showed highly stereoselective cell uptake with several substrates and, interestingly, often with opposite stereoselectivity. In contrast, transport by OCT1 was less stereoselective, although ( R )-tamsulosin was transported by OCT1 with higher apparent affinity than the ( S )-enantiomer. Using OCT1 and CYP2D6 co-overexpressing cells, an additive effect of the stereoselectivities was demonstrated. This indicates that pharmacokinetic stereoselectivity may be the result of combined effects in transport and metabolism. This study highlights that the pronounced polyspecificity of OCTs not contradicts stereoselectivity in the transport. Nevertheless, stereoselectivity is highly substrate-specific and for most substrates and OCTs, there was no major selectivity.

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“…Substances with two strongly positively charged groups localized about 10 Å apart in the molecule are also non-typical substrates of OCT1, which are impressively demonstrated by the strong OCT1 inhibitor chlorhexidine and related agents [ 33 ]. In part, this might be simply explained by the unspecific detergent-like effect of these molecules.…”

Section: Discussionmentioning

confidence: 99%

Atypical Substrates of the Organic Cation Transporter 1

et al. 2022

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The human organic cation transporter 1 (OCT1) is expressed in the liver and mediates hepatocellular uptake of organic cations. However, some studies have indicated that OCT1 could transport neutral or even anionic substrates. This capability is interesting concerning protein-substrate interactions and the clinical relevance of OCT1. To better understand the transport of neutral, anionic, or zwitterionic substrates, we used HEK293 cells overexpressing wild-type OCT1 and a variant in which we changed the putative substrate binding site (aspartate474) to a neutral amino acid. The uncharged drugs trimethoprim, lamivudine, and emtricitabine were good substrates of hOCT1. However, the uncharged drugs zalcitabine and lamotrigine, and the anionic levofloxacin, and prostaglandins E2 and F2α, were transported with lower activity. Finally, we could detect only extremely weak transport rates of acyclovir, ganciclovir, and stachydrine. Deleting aspartate474 had a similar transport-lowering effect on anionic substrates as on cationic substrates, indicating that aspartate474 might be relevant for intra-protein, rather than substrate-protein, interactions. Cellular uptake of the atypical substrates by the naturally occurring frequent variants OCT1*2 (methionine420del) and OCT1*3 (arginine61cysteine) was similarly reduced, as it is known for typical organic cations. Thus, to comprehensively understand the substrate spectrum and transport mechanisms of OCT1, one should also look at organic anions.

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Substrates and Inhibitors of the Organic Cation Transporter 3 and Comparison with OCT1 and OCT2

Cited by 14 publications

References 42 publications

Stereoselective Inhibition of High- and Low-Affinity Organic Cation Transporters

Stereoselective Inhibition of High- and Low-Affinity Organic Cation Transporters

Stereoselectivity in Cell Uptake by SLC22 Organic Cation Transporters 1, 2, and 3

Atypical Substrates of the Organic Cation Transporter 1

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