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

2021 ◽  
Vol 11 ◽  
Author(s):  
Ole Jensen ◽  
Muhammad Rafehi ◽  
Lukas Gebauer ◽  
Jürgen Brockmöller
Keyword(s):  
Cellular Uptake ◽  
Adverse Reactions ◽  
Organic Cation ◽  
Interindividual Variation ◽  
Monoamine Transporters ◽  
Organic Cation Transporters ◽  
Naturally Occurring ◽  
Cation Transporters ◽  
Drug Traffickers

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.

Abstract 14035: Renal Tubular Secretion and Cardiac Distribution of Dofetilide is Dependent on MATE1 Function

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Muhammad Erfan Uddin ◽  
Yan Jin ◽  
Alice A Gibson ◽  
Ingrid M Bonilla ◽  
Cynthia A Carnes ◽  
...  
Keyword(s):  
Organic Cation ◽  
Tubular Secretion ◽  
Hek293 Cells ◽  
Delayed Rectifier ◽  
Organic Cation Transporters ◽  
Wild Type ◽  
Renal Tubular Secretion ◽  
Cation Transporters ◽  
Renal Tubular

Introduction: Dofetilide is a delayed rectifier potassium channel inhibitor used to treat patients with atrial fibrillation and flutter, and its use is associated with a risk of QT prolongation and Torsades de Pointes . The mechanisms involved in dofetilide’s renal tubular secretion and its uptake into cardiomyocytes remain unknown. Previously reported drug-drug interaction (DDI) studies suggest the involvement of organic cation transporters. Here, we investigated the contribution of organic cation transporters (OCT2 and MATE1) to the pharmacokinetics of dofetilide to gain insight into its DDI potential. Hypothesis: Based on known DDIs with dofetilide, we hypothesize that OCT2 and/or MATE1 play a key role in the inter-individual variability in pharmacokinetics and pharmacodynamics of dofetilide. Methods: In vitro and ex vivo transport kinetics of dofetilide were determined in HEK293 cells stably transfected with OCT2 or MATE1, and in isolated cardiomyocytes, respectively. In vivo studies were performed in wild-type, OCT2-, and MATE1-deficient mice (n=5) receiving dofetilide (5 mg/kg, p.o., 2.5 mg/kg, i.v.), with or without several contraindicated drugs. Dofetilide concentrations in plasma and urine were determined by UPLC-MS/MS. Results: In vitro studies demonstrated that dofetilide is a good substrate of MATE1 but not OCT2. Deficiency of MATE1 was associated with increased plasma concentrations of dofetilide and with a significantly reduced urinary excretion (3-fold in females and 5-fold in males, respectively). Dofetilide accumulation in cardiomyocytes was increased by 2-fold in MATE1-deficient females, and pre-incubation with the MATE1 inhibitor cimetidine significantly reduced dofetilide uptake in wild-type cardiomyocytes. Several contraindicated drugs listed in the dofetilide prescribing information, including cimetidine, ketoconazole, increased dofetilide plasma exposure in wild-type mice by >2.8-fold. Conclusion: Renal secretion of dofetilide is mediated by MATE1 and is highly sensitive to inhibition by many widely used prescription drugs that can cause clinically relevant DDIs. Deficiency of MATE1 also increases accumulation in the heart which may contribute to individual variation in response to dofetilide.

scholarly journals Interaction Profiles of Central Nervous System Active Drugs at Human Organic Cation Transporters 1–3 and Human Plasma Membrane Monoamine Transporter

2021 ◽  
Vol 22 (23) ◽  
pp. 12995
Author(s):  
Thomas J. F. Angenoorth ◽  
Stevan Stankovic ◽  
Marco Niello ◽  
Marion Holy ◽  
Simon D. Brandt ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Plasma Membrane ◽  
Human Plasma ◽  
Organic Cation ◽  
Hek293 Cells ◽  
Monoamine Transporters ◽  
Organic Cation Transporters ◽  
Monoamine Transporter ◽  
Cation Transporters

Many psychoactive compounds have been shown to primarily interact with high-affinity and low-capacity solute carrier 6 (SLC6) monoamine transporters for norepinephrine (NET; norepinephrine transporter), dopamine (DAT; dopamine transporter) and serotonin (SERT; serotonin transporter). Previous studies indicate an overlap between the inhibitory capacities of substances at SLC6 and SLC22 human organic cation transporters (SLC22A1–3; hOCT1–3) and the human plasma membrane monoamine transporter (SLC29A4; hPMAT), which can be classified as high-capacity, low-affinity monoamine transporters. However, interactions between central nervous system active substances, the OCTs, and the functionally-related PMAT have largely been understudied. Herein, we report data from 17 psychoactive substances interacting with the SLC6 monoamine transporters, concerning their potential to interact with the human OCT isoforms and hPMAT by utilizing radiotracer-based in vitro uptake inhibition assays at stably expressing human embryonic kidney 293 cells (HEK293) cells. Many compounds inhibit substrate uptake by hOCT1 and hOCT2 in the low micromolar range, whereas only a few substances interact with hOCT3 and hPMAT. Interestingly, methylphenidate and ketamine selectively interact with hOCT1 or hOCT2, respectively. Additionally, 3,4-methylenedioxymethamphetamine (MDMA) is a potent inhibitor of hOCT1 and 2 and hPMAT. Enantiospecific differences of R- and S-α-pyrrolidinovalerophenone (R- and S-α-PVP) and R- and S-citalopram and the effects of aromatic substituents are explored. Our results highlight the significance of investigating drug interactions with hOCTs and hPMAT, due to their role in regulating monoamine concentrations and xenobiotic clearance.

Differential pharmacological in vitro properties of organic cation transporters and regional distribution in rat brain

2006 ◽  
Vol 50 (8) ◽  
pp. 941-952 ◽  
Author(s):  
Anne Amphoux ◽  
Vincent Vialou ◽  
Eva Drescher ◽  
Michael Brüss ◽  
Clotilde Mannoury La Cour ◽  
...  
Keyword(s):  
Rat Brain ◽  
Organic Cation ◽  
Regional Distribution ◽  
Organic Cation Transporters ◽  
Cation Transporters

Multiple binding sites in organic cation transporters require sophisticated procedures to identify interactions of novel drugs

2019 ◽  
Vol 400 (2) ◽  
pp. 195-207 ◽  
Author(s):  
Hermann Koepsell
Keyword(s):  
Binding Sites ◽  
Organic Cation ◽  
Cation Binding ◽  
Organic Cation Transporters ◽  
High Affinity ◽  
Multiple Binding Sites ◽  
Novel Drugs ◽  
Cation Transporters ◽  
Influence Of Substrate

AbstractIn vitroevaluation of drugs for interaction with transporters is essential during drug development. As polyspecific organic cation transporters (OCTs) are critical for pharmacokinetics of many cationic drugs,in vitrotesting of human OCT1 and human OCT2 is recommended. In the currently applied tests it is determined whether uptake of one model cation in stably transfected epithelial cells is inhibited using a substrate concentration in the micromolar range. In this review experimental evidence for the existence of low- and high-affinity cation binding sites in OCTs that may interact with drugs is compiled. Most data were obtained from studies performed with rat Oct1. Whereas overlapping low-affinity cation binding sites are directly involved in transport, the high-affinity cation binding sites may induce allosteric inhibition of transport. Remarkably, high-affinity inhibition is only observed when uptake is measured using nanomolar substrate concentrations far below the respectiveKmvalues. Affinities of inhibitors are dependent on molecular structure and concentration of the employed substrate. Because the currently appliedin vitrotests for identification of interaction of novel drugs with OCTs do not consider the influence of substrate structure and are not capable of identifying high-affinity inhibition, more sophisticated testing protocols are proposed.

Nitric oxide-induced regulation of renal organic cation transport after renal ischemia-reperfusion injury

2011 ◽  
Vol 301 (5) ◽  
pp. F997-F1004 ◽  
Author(s):  
R. Schneider ◽  
M. Meusel ◽  
B. Betz ◽  
M. Kersten ◽  
K. Möller-Ehrlich ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Organic Cation ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Fractional Excretion ◽  
Renal Ischemia ◽  
Organic Cation Transporters ◽  
Cation Transporters

Renal organic cation transporters are downregulated by nitric oxide (NO) in rat endotoxemia. NO generated by inducible NO synthase (iNOS) is substantially increased in the renal cortex after renal ischemia-reperfusion (I/R) injury. Therefore, we investigated the effects of iNOS-specific NO inhibition on the expression of the organic cation transporters rOct1 and rOct2 (Slc22a1 and Slc22a2, respectively) after I/R injury both in vivo and in vitro. In vivo, N6-(1-iminoethyl)-l-lysine (l-NIL) completely inhibited NO generation after I/R injury. Moreover, l-NIL abolished the ischemia-induced downregulation of rOct1 and rOct2 as determined by qPCR and Western blotting. Functional evidence was obtained by measuring the fractional excretion (FE) of the endogenous organic cation serotonin. Concordant with the expression of the rate-limiting organic cation transporter, the FE of serotonin decreased after I/R injury and was totally abolished by l-NIL. In vitro, ischemia downregulated both rOct1 and rOct2, which were also abolished by l-NIL; the same was true for the uptake of the organic cation MPP. We showed that renal I/R injury downregulates rOct1 and rOct2, which is most probably mediated via NO. In principle, this may be an autocrine effect of proximal tubular epithelial cells. We conclude that rOct1, or rOct1 and rOct2 limit the rate of the renal excretion of serotonin.

scholarly journals Overlap and Specificity in the Substrate Spectra of Human Monoamine Transporters and Organic Cation Transporters 1, 2, and 3

2021 ◽  
Vol 22 (23) ◽  
pp. 12816
Author(s):  
Lukas Gebauer ◽  
Ole Jensen ◽  
Maria Neif ◽  
Jürgen Brockmöller ◽  
Christof Dücker
Keyword(s):  
Organic Cation ◽  
Signal Transmission ◽  
Cell Uptake ◽  
Hek293 Cells ◽  
Monoamine Transporters ◽  
Organic Cation Transporters ◽  
Structural Determinants ◽  
Renal Drug Elimination ◽  
The Central Nervous System ◽  
Cation Transporters

Human monoamine transporters (MATs) are cation transporters critically involved in neuronal signal transmission. While inhibitors of MATs have been intensively studied, their substrate spectra have received far less attention. Polyspecific organic cation transporters (OCTs), predominantly known for their role in hepatic and renal drug elimination, are also expressed in the central nervous system and might modulate monoaminergic signaling. Using HEK293 cells overexpressing MATs or OCTs, we compared uptake of 48 compounds, mainly phenethylamine and tryptamine derivatives including matched molecular pairs, across noradrenaline, dopamine and serotonin transporters and OCTs (1, 2, and 3). Generally, MATs showed surprisingly high transport activities for numerous analogs of neurotransmitters, but their substrate spectra were limited by molar mass. Human OCT2 showed the broadest substrate spectrum, and also the highest overlap with MATs substrates. Comparative kinetic analyses revealed that the radiotracer meta-iodobenzylguanidine had the most balanced uptake across all six transporters. Matched molecular pair analyses comparing MAT and OCT uptake using the same methodology could provide a better understanding of structural determinants for high cell uptake by MATs or OCTs. The data may result in a better understanding of pharmacokinetics and toxicokinetics of small molecular organic cations and, possibly, in the development of more specific radiotracers for MATs.

Sign in / Sign up

Export Citation Format

Share Document