Movement of Hydroxyurea Across Cell Membranes Is Mediated by Specific Solute Carrier (SLC) Transporters.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2575-2575
Author(s):  
Aisha L. Walker ◽  
Ryan M Franke ◽  
Alex Sparreboom ◽  
Russell E. Ware
Keyword(s):  
Vector Control ◽  
Cellular Uptake ◽  
Organic Cation ◽  
Organic Anion ◽  
Fold Increase ◽  
The Body ◽  
Transcellular Transport ◽  
Slc Transporters ◽  
Solute Carrier

Abstract Abstract 2575 Poster Board II-552 Background: Hydroxyurea is the only FDA-approved drug for the treatment of sickle cell anemia (SCA) in adults. Hydroxyurea increases fetal hemoglobin, decreases hospitalizations and painful events, and reduces mortality. With an oral bioavailability of > 90%, hydroxyurea is rapidly absorbed and distributed throughout the body. Though hydroxyurea has proven to be effective in treating SCA, there is considerable inter-patient variability observed in the pharmacokinetics and pharmacodynamics of hydroxyurea. Currently, mechanisms involved in the absorption, distribution, and elimination of hydroxyurea remain unclear. Recently, key transmembrane proteins have been identified as drug transporters due to their ability to move a variety of xenobiotic substances across cell membranes. Drug transporters are widely distributed throughout the body, and most are specific to certain substrates. Solute carrier (SLC) transporters in particular have been to shown to significantly impact drug pharmacokinetics by influencing the absorption, distribution, and elimination of specific drugs. The present study was designed to identify SLC transporters that may influence the absorption, distribution, and/or elimination of hydroxyurea in patients with SCA. Methods: In vitro studies using an equilibrium dialysis plate were performed to determine the amount of hydroxyurea that binds to human serum proteins. Transporter-mediated cellular uptake of hydroxyurea was determined in vitro by measuring [14C]-hydroxyurea accumulation in HEK293 cells and oocytes that overexpress organic anion transporters (OAT1-3), organic cation transporters (OCT1-3), organic cation/carnitine transporters (OCTN1-2), organic anion transporting polypeptides (OATP1A2/OATP1B1/OATP1B3), or vector control. LLC-PK1 cells that overexpress urea transporters A or B (UTA/UTB) were used to determine UTA/UTB mediated transcellular transport of hydroxyurea in transwell plates. The transport of [14C]-hydroxyurea from apical to basal or from basal to apical compartments was measured for the UTA/UTB overexpressing cells and compared to vector control. UTA and UTB mRNA expression was measured by real-time PCR of cDNA obtained from human tissue samples. Results: Protein binding assays showed that >76% of [14C]-hydroxyurea remained unbound to proteins in human serum containing hydroxyurea at concentrations ranging from 1.5μM to 500μM. The fraction of unbound hydroxyurea was similar using serum obtained from pediatric patients with SCA. In uptake studies, [14C]-hydroxyurea was a potent substrate for OATP1B3 with an approximately 2-fold increase in drug accumulation compared to control (p<0.001). In contrast, hydroxyurea was found to be a weak substrate for OCTN1, OCTN2, OATP1A2, and OATP1B1 with only a 1.3-fold increase in drug accumulation compared to control (p<0.04). Transcellular transport of hydroxyurea was increased 3- and 2-fold by UTA and UTB, respectively, compared to vector control demonstrating hydroxyurea to be a potent substrate for these transporters as well (p<0.02). When the urea transporter inhibitor dimethylurea was added, hydroxyurea transport by UTA and UTB-expressing cells was decreased to levels observed with the vector control. In real-time PCR assays, kidney, muscle, and small intestine were among human tissues with high expression of UTA mRNA, while prostate, brain, and bone marrow had high levels of UTB mRNA expression. Conclusion: Cellular uptake of hydroxyurea is mediated by active transport via specific SLC transporters OATP1B3, UTA and UTB, which are expressed in liver, kidney, brain, intestine, and blood cells. Studies to further characterize hydroxyurea transporters should improve our understanding of the pharmacokinetic and pharmacodynamic profiles of hydroxyurea used in clinical practice for patients with SCA. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Antitubercular Agent Delamanid and Metabolites as Substrates and Inhibitors of ABC and Solute Carrier Transporters

2016 ◽  
Vol 60 (6) ◽  
pp. 3497-3508 ◽  
Author(s):  
Hiroyuki Sasabe ◽  
Yoshihiko Shimokawa ◽  
Masakazu Shibata ◽  
Kenta Hashizume ◽  
Yusuke Hamasako ◽  
...  
Keyword(s):  
Abc Transporters ◽  
Organic Anion ◽  
Organic Cation Transporter ◽  
Multidrug Resistant ◽  
Inhibitory Effect ◽  
Cancer Resistance ◽  
Slc Transporters ◽  
Solute Carrier ◽  
Multiple Drugs

Delamanid (Deltyba, OPC-67683) is the first approved drug in a novel class of nitro-dihydro-imidazooxazoles developed for the treatment of multidrug-resistant tuberculosis. Patients with tuberculosis require treatment with multiple drugs, several of which have known drug-drug interactions. Transporters regulate drug absorption, distribution, and excretion; therefore, the inhibition of transport by one agent may alter the pharmacokinetics of another, leading to unexpected adverse events. Therefore, it is important to understand how delamanid affects transport activity. In the present study, the potencies of delamanid and its main metabolites as the substrates and inhibitors of various transporters were evaluatedin vitro. Delamanid was not transported by the efflux ATP-binding cassette (ABC) transporters P-glycoprotein (P-gp; MDR1/ABCB1) and breast cancer resistance protein (BCRP/ABCG2), solute carrier (SLC) transporters, organic anion-transporting polypeptides, or organic cation transporter 1. Similarly, metabolite 1 (M1) was not a substrate for any of these transporters except P-gp. Delamanid showed no inhibitory effect on ABC transporters MDR1, BCRP, and bile salt export pump (BSEP; ABCB11), SLC transporters, or organic anion transporters. M1 and M2 inhibited P-gp- and BCRP-mediated transport but did so only at the 50% inhibitory concentrations (M1, 4.65 and 5.71 μmol/liter, respectively; M2, 7.80 and 6.02 μmol/liter, respectively), well above the corresponding maximum concentration in plasma values observed following the administration of multiple doses in clinical trials. M3 and M4 did not affect the activities of any of the transporters tested. Thesein vitrodata suggest that delamanid is unlikely to have clinically relevant interactions with drugs for which absorption and disposition are mediated by this group of transporters.

scholarly journals Uptake Transporters of the SLC21, SLC22A, and SLC15A Families in Anticancer Therapy—Modulators of Cellular Entry or Pharmacokinetics?

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2263 ◽  
Author(s):  
Karin Brecht ◽  
Anima Magdalena Schäfer ◽  
Henriette E. Meyer zu Schwabedissen
Keyword(s):  
Kinase Inhibitors ◽  
Organic Cation ◽  
Organic Anion ◽  
Large Family ◽  
Cancer Therapeutics ◽  
Anion Transporters ◽  
Slc Transporters ◽  
Solute Carrier ◽  
Endogenous Substrates ◽  
Uptake Transporters

Solute carrier transporters comprise a large family of uptake transporters involved in the transmembrane transport of a wide array of endogenous substrates such as hormones, nutrients, and metabolites as well as of clinically important drugs. Several cancer therapeutics, ranging from chemotherapeutics such as topoisomerase inhibitors, DNA-intercalating drugs, and microtubule binders to targeted therapeutics such as tyrosine kinase inhibitors are substrates of solute carrier (SLC) transporters. Given that SLC transporters are expressed both in organs pivotal to drug absorption, distribution, metabolism, and elimination and in tumors, these transporters constitute determinants of cellular drug accumulation influencing intracellular drug concentration required for efficacy of the cancer treatment in tumor cells. In this review, we explore the current understanding of members of three SLC families, namely SLC21 (organic anion transporting polypeptides, OATPs), SLC22A (organic cation transporters, OCTs; organic cation/carnitine transporters, OCTNs; and organic anion transporters OATs), and SLC15A (peptide transporters, PEPTs) in the etiology of cancer, in transport of chemotherapeutic drugs, and their influence on efficacy or toxicity of pharmacotherapy. We further explore the idea to exploit the function of SLC transporters to enhance cancer cell accumulation of chemotherapeutics, which would be expected to reduce toxic side effects in healthy tissue and to improve efficacy.

scholarly journals Comprehensive Substrate Characterization of 22 Antituberculosis Drugs for Multiple Solute Carrier (SLC) Uptake TransportersIn Vitro

2018 ◽  
Vol 62 (9) ◽  
Author(s):  
M. M. Parvez ◽  
Nazia Kaisar ◽  
Ho Jung Shin ◽  
Yoon Jae Lee ◽  
Jae-Gook Shin
Keyword(s):  
Drug Interactions ◽  
Organic Anion ◽  
Organic Anion Transporter ◽  
Antituberculosis Drugs ◽  
Hek 293 ◽  
Slc Transporters ◽  
Anion Transporter ◽  
Solute Carrier

ABSTRACTThe substrate potentials of antituberculosis drugs on solute carrier (SLC) transporters are not well characterized to date, despite a well-established understanding of their drug dispositions and pharmacokinetics. In this study, we investigated comprehensively the substrate potentials of the 22 currently available antituberculosis drugs for SLC family transporter-mediated uptake, usingXenopus laevisoocytes and stably transfected HEK-293 cellsin vitro. The result suggested that ethambutol, isoniazid, amoxicillin, and prothionamide act as novel substrates for the SLC transporters. In addition, in the presence of representative transporter inhibitors, the uptake of the antituberculosis drugs was markedly decreased compared with the uptake in the absence of inhibitor, suggesting involvement of the corresponding transporters. A cellular uptake study was performed, and theKmvalues of ethambutol were found to be 526.1 ± 15.6, 212.0 ± 20.1, 336.8 ± 20.1, and 455.0 ± 28 μM for organic cation transporter 1 (OCT1), OCT2, OCTN1, and OCTN2, respectively. Similarly, theKmof prothionamide was 805.8 ± 23.4 μM for OCT1, while theKmvalues of isoniazid and amoxicillin for organic anion transporter 3 (OAT3) were 233.7 ± 14.1 and 161.4 ± 10.6 μM, respectively. The estimatedin vivodrug-drug interaction indexes fromin vitrotransporter inhibition kinetics for verapamil, probenecid, and ibuprofen against ethambutol, prothionamide, isoniazid, and amoxicillin were found to show potential for clinical drug interactions. In conclusion, this is the first study that demonstrated 22 antituberculosis drug interactions with transporters. This study will be helpful for mechanistic understanding of the disposition, drug-drug interactions, and pharmacokinetics of these antituberculosis drugs.

scholarly journals Zinc and the Zinc Transporter SLC39A10/ZIP10 Are Required for Heme Synthesis in Developing Erythroid Progenitors

2021 ◽  
Vol 5 (Supplement_2) ◽  
pp. 1320-1320
Author(s):  
Juyoung Kim ◽  
Jaekwon Lee ◽  
Moon-Suhn Ryu
Keyword(s):  
In Vitro Study ◽  
Fold Increase ◽  
Zinc Transporter ◽  
The Body ◽  
Zinc Homeostasis ◽  
Mean Corpuscular Hemoglobin ◽  
Erythroid Progenitors ◽  
Heme Synthesis ◽  
Cellular Zinc

Abstract Objectives Zinc is an essential nutrient for diverse biological processes in the body. Cellular zinc homeostasis is established through differential expressions of the transmembrane zinc transporter proteins, ZnTs and ZIPs. The aims of the current studies were to elucidate the roles of cellular zinc in erythrocyte maturation, and to determine the zinc transporters essential to erythroid zinc homeostasis. Methods G1E-ER4 mouse cells were employed as an in vitro study model of terminal erythroid differentiation. A cell-impermeable zinc chelator, diethylenetriamine pentaacetate (DTPA), was used to limit extracellular zinc availability. For gene silencing, gene-specific siRNAs were introduced to cells via Nucleofection. Functional impacts of zinc and gene deficiency were assessed via ICP-MS-based metal quantitation, heme assays, and gene expression assays using RNA-seq, qPCR, and western analyses. Results G1E-ER4 cells featured a 1.7-fold increase in total cellular zinc contents after 48 h of differentiation. Restriction of zinc import by 50 µM of DTPA led to less red coloration and lower increases in mean corpuscular hemoglobin contents by development. The heme deficiency by DTPA was fully restored by the addition of equimolar zinc, and was not due to changes in cellular iron contents. Zinc-deficient G1E-ER4 cells differentiated with normal Alas2 and Hbb-b1 transcript responses, but less Alad and alpha-globin expressions. Among the 24 zinc transporter genes, Zip10 produced the most prominent response to zinc restriction in differentiating erythroid cells. ZIP10-deficient G1E-ER4 cells were less efficient than control cells in hemoglobin production under zinc restriction. ZIP10 deficiency alone had no effects on the molecular indices of red cell hemoglobinization. Conclusions Our studies characterize zinc as a nutrient essential to normal erythroid maturation and heme synthesis. Moreover, we have identified a compensatory role of ZIP10 for erythroid zinc homeostasis during zinc restriction. Thus, poor zinc status and ZIP10 mutations might serve as potential risk factors and thus new therapeutic targets for anemia and other erythrocyte-related disorders. Funding Sources Supported by CFANS Graduate Fellowship to JK, and the Allen Foundation, Inc. and USDA NIFA Hatch Funds to M-SR.

scholarly journals Preclinical evaluation of new α-radionuclide therapy targeting LAT1: 2-[211At]astato-α-methyl-L-phenylalanine in tumor-bearing model

2020 ◽  
Author(s):  
Yasuhiro OHSHIMA ◽  
Hiroyuki Suzuki ◽  
Hirofumi Hanaoka ◽  
Ichiro Sasaki ◽  
Shigeki Watanabe ◽  
...  
Keyword(s):  
Cellular Uptake ◽  
Radionuclide Therapy ◽  
Cancer Cell Line ◽  
Strand Break ◽  
The Body ◽  
Cellular Growth ◽  
Dna Double Strand Break ◽  
Amino Acid Analog

Abstract PURPOSE: Targeted α-radionuclide therapy has growing attention as a promising therapy for refractory cancers. However, the application is limited to certain types of cancer. Since L-type amino acids transporter 1 (LAT1) is highly expressed in various human cancers, we prepared LAT1-selective α-emitting amino acid analog, 2-[211At]astato-α-methyl-L-phenylalanine ([211At]-2-AAMP), and evaluated its potential as a therapeutic agent. METHODS: [211At]-2-AAMP was prepared from the stannyl precursor. Stability of [211At]-2-AAMP was evaluated by both in vitro and in vivo. In vitro studies using LAT1 expressing human ovary cancer cell line, SKOV3, were performed for evaluating cellular uptake and cytotoxicity of [211At]-2-AAMP. Biodistribution and therapeutic studies in SKOV3 bearing mice were performed after intravenous injection of [211At]-2-AAMP. RESULTS: [211At]-2-AAMP was stable in murine plasma in vitro and excreted into urine as intact. Cellular uptake of [211At]-2-AAMP was inhibited by treatment with LAT1-selective inhibitor. After 24 hours of incubation, [211At]-2-AAMP suppressed clonogenic growth at 10 kBq/ml, and induced cell death and DNA double strand break at 25 kBq/ml. When injected to mice, [211At]-2-AAMP exhibited the peak accumulation in the tumor at 30 min postinjection, and the radioactivity levels in the tumor retained up to 60 min. The majority of the radioactivity was rapidly eliminated from the body into the urine as an intact form immediately after injection. [211At]-2-AAMP significantly improved the survival of mice (P<0.05) without serious side effects. CONCLUSION: [211At]-2-AAMP showed α-radiation-dependent cellular growth inhibition after taking up via LAT1. Furthermore, [211At]-2-AAMP provided a beneficial effect on survival in vivo. These findings suggest that [211At]-2-AAMP might be useful for treatment of LAT1-positive cancer.

scholarly journals Optimization and Evaluation of Poly(lactide-co-glycolide) Nanoparticles for Enhanced Cellular Uptake and Efficacy of Paclitaxel in the Treatment of Head and Neck Cancer

Pharmaceutics ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 828
Author(s):  
Mohamed Haider ◽  
Amr Elsherbeny ◽  
Jayalakshmi Jagal ◽  
Anna Hubatová-Vacková ◽  
Iman Saad Ahmed
Keyword(s):  
Cellular Uptake ◽  
Fold Increase ◽  
Systemic Circulation ◽  
Free Drug ◽  
Carcinoma Cells ◽  
Spherical Particles ◽  
In Vitro Drug Release ◽  
Formulation Parameters ◽  
Drug Solution

The particle size (PS) and encapsulation efficiency (EE%) of drug-loaded nanoparticles (NPs) may inhibit their cellular uptake and lead to possible leakage of the drug into the systemic circulation at the tumor site. In this work, ultra-high paclitaxel-loaded poly(lactide-co-glycolide) NPs (PTX-PLGA-NPs) with ultra-small sizes were prepared and optimized by adopting the principles of quality by design (QbD) approach. The optimized PTX-PLGA-NPs showed ultra-small spherical particles of about 53 nm with EE% exceeding 90%, a relatively low polydispersity index (PDI) of 0.221, an effective surface charge of −10.1 mV, and a 10-fold increase in the in vitro drug release over 72 h relative to free drug. The cellular viability of pharynx carcinoma cells decreased by almost 50% in 24 h following treatment with optimized PTX-PLGA-NPs, compared to only 20% from the free drug. The intracellular uptake of PTX-PLGA-NPs was highly favored, and the antitumor activity of PTX was remarkably improved with a reduction in its half maximal inhibitory concentration (IC50), by almost 50% relative to free drug solution. These results suggest that the optimal critical formulation parameters, guided by QbD principles, could produce PLGA-NPs with remarkably high EE% and ultra-small PS, resulting in enhanced cellular uptake and efficacy of PTX.

NANO-BIOTECHNOLOGY AND ITS INNOVATIVE PERSPECTIVE IN DIABETES MANAGEMENT

2021 ◽  
Vol 21 ◽  
Author(s):  
Jigar Raval ◽  
Riddhi Trivedi ◽  
Sonali Suman ◽  
Arvind Kukrety ◽  
Prajesh Prajapati
Keyword(s):  
Cellular Uptake ◽  
Glucose Homeostasis ◽  
Diabetes Management ◽  
The Body ◽  
Paracellular Transport ◽  
Specific Gene ◽  
Future Prospects ◽  
Transcellular Transport ◽  
Routes Of Administration ◽  
Two Stages

: Diabetes occurs due to the imbalance of glucose in the body known as glucose homeostasis, thus leading to metabolic changes in the body. The two stages hypoglycemia or hyperglycemia classify diabetes into various categories. Various bio-nanotechnological approaches are coupled up with nano particulates, polymers, liposome, various gold plated and solid lipid particulates, regulating transcellular transport, non specific cellular uptake, and paracellular transport, leading to oral, trans-dermal , pulmonary, buccal , nasal , specific gene oriented administration to avoid the patient’s non compliance with the parental routes of administration. Phytochemicals are emerging strategies for the future prospects of diabetes management.

Organic Cation Transporters are Involved in Fluoxetine Transport Across the Blood-Brain Barrier in Vivo and in Vitro

2021 ◽  
Vol 18 ◽  
Author(s):  
Min Wang ◽  
Yingying Sun ◽  
Bingying Hu ◽  
Zhisheng He ◽  
Shanshan Chen ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Cellular Uptake ◽  
Organic Cation ◽  
Brain Barrier ◽  
Organic Cation Transporters ◽  
Cellular Accumulation ◽  
Blood Brain ◽  
The Brain

Background : The research and development of drugs for the treatment of central nervous system diseases faces many challenges at present. One of the most important questions to be answered is, how does the drug cross the blood-brain barrier to get to the target site for pharmacological action. Fluoxetine is widely used in clinical antidepressant therapy. However, the mechanism by which fluoxetine passes through the BBB also remains unclear. Under physiological pH conditions, fluoxetine is an organic cation with a relatively small molecular weight (<500), which is in line with the substrate characteristics of organic cation transporters (OCTs). Therefore, this study aimed to investigate the interaction of fluoxetine with OCTs at the BBB and BBB-associated efflux transporters. This is of great significance for fluoxetine to better treat depression. Moreover, it can provide a theoretical basis for clinical drug combinations. Methods: In vitro BBB model was developed using human brain microvascular endothelial cells (hCMEC/D3), and the cellular accumulation was tested in the presence or absence of transporter inhibitors. In addition, an in vivo trial was performed in rats to investigate the effect of OCTs on the distribution of fluoxetine in the brain tissue. Fluoxetine concentration was determined by a validated UPLC-MS/MS method. Results: The results showed that amantadine (an OCT1/2 inhibitor) and prazosin (an OCT1/3 inhibitor) significantly decreased the cellular accumulation of fluoxetine (P <.001). Moreover, we found that N-methylnicotinamide (an OCT2 inhibitor) significantly inhibited the cellular uptake of 100 and 500 ng/mL fluoxetine (P <.01 and P <.05 respectively). In contrast, corticosterone (an OCT3 inhibitor) only significantly inhibited the cellular uptake of 1000 ng/mL fluoxetine (P <.05). The P-glycoprotein (P-gp) inhibitor, verapamil, and the multidrug resistance resistance-associated proteins (MRPs) inhibitor, MK571, significantly decreased the cellular uptake of fluoxetine. However, intracellular accumulation of fluoxetine was not significantly changed when fluoxetine was incubated with the breast cancer resistance protein (BCRP) inhibitor Ko143. Furthermore, in vivo experiments proved that corticosterone and prazosin significantly inhibited the brain-plasma ratio of fluoxetine at 5.5 h and 12 h, respectively. Conclusion: OCTs might play a significant role in the transport of fluoxetine across the BBB. In addition, P-gp, BCRP, and MRPs seemed not to mediate the efflux transport of fluoxetine.

scholarly journals Metabolism and pharmacokinetics of a novel polyphenol fatty acid ester phloridzin docosahexaenoate in Balb/c female mice

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Wasundara Fernando ◽  
Kerry B. Goralski ◽  
David W. Hoskin ◽  
H. P. Vasantha Rupasinghe
Keyword(s):  
Fatty Acid ◽  
Cellular Uptake ◽  
Fatty Acid Ester ◽  
Acid Ester ◽  
Biological Effects ◽  
The Body ◽  
Pharmacokinetic Parameters ◽  
Female Mice ◽  
Organ Systems

AbstractFlavonoids are known to undergo phase II metabolism and produce metabolites with similar or stronger biological effects compared to the parent flavonoids. However, the limited cellular uptake and bioavailability restrict their clinical use. We synthesized phloridzin docosahexaenoate (PZ-DHA), a novel fatty acid ester of polyphenol, through an acylation reaction with the aim of increasing the cellular availability and stability of the parent biomolecules, phloridzin (PZ) and docosahexaenoic acid (DHA). Here, we report metabolites and pharmacokinetic parameters of PZ-DHA, determined using ultra-high-performance liquid chromatography-electrospray ionization tandem mass spectrometry. PZ-DHA was taken-up by human (MDA-MB-231, MDA-MB-468, and MCF-7) and mouse (4T1) mammary carcinoma and human non-malignant mammary epithelial cells (MCF-10A) in cellular uptake assays. Our results suggested that the acylation improves the cellular uptake of PZ and stability of DHA within cells. In mouse hepatic microsomal assays, two major glucuronides of PZ-DHA, PZ-DHA-4-O-glucuronide and PZ-DHA-4′-O-glucuronide (MW = 923.02 g/mol), were detected. One tri-methylated- (4,4′,6′-O-trimethyl-PZ-DHA) (MW = 788.88 g/mol) and one di-sulphated- (PZ-DHA-4,4′-O-disulphide) PZ-DHA metabolite (MW = 906.20 g/mol) were also identified. Intraperitoneal injections of PZ-DHA (100 mg/kg) into Balb/c female mice was rapidly absorbed with a serum Cmax and Tmax of 23.7 µM and 60 min, respectively, and rapidly eliminated (t1/2 = 28.7 min). PZ-DHA and its metabolites are readily distributed throughout the body (Vd = 57 mL) into many organs. We identified in vitro and in vivo metabolites of PZ-DHA, which could be tested for potential use to treat diseases such as cancer in multiple organ systems.

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.

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