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Challenges and Perspectives of Drug Transporters: Where Do We Go...
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Challenges and Perspectives of Drug Transporters: Where Do We Go from Here?

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Pharmacokinetics and Pharmacodynamics".

Deadline for manuscript submissions: closed (20 February 2023) | Viewed by 27734

Special Issue Editor

Prof. Dr. Stefan Oswald

E-Mail Website1 Website2
Guest Editor
Institute of Pharmacology and Toxicology, Rostock University Medical Center, 18051 Rostock, Germany
Interests: drug transporters; drug metabolizing enzymes; intestine; bioanalytics

Special Issue Information

Dear Colleagues,

During the last decades, drug transporters have been identified as important determinants of the pharmacokinetics and, in turn, the pharmacodynamics of many drugs. Prominent and well-characterized examples in this regard are P-gp, BCRP, OATP1B1, and OATs, mediating the uptake or efflux of drugs and/or their metabolites in intestine, liver, and kidney. Inhibition or induction of drug transporters can lead to serious unwanted drug–drug interactions, while genetic polymorphisms may result in substantial inter-individual variability, which are both of clinical relevance for the efficacy and safety of their respective substrates. Consequently, drug transporters for new molecular entities have to be considered in today’s drug development programs, according to recent guidelines from the medical authorities.

However, our current knowledge is still limited to some 20–30 transporters, whereas we know today about 50 ABC and 400 SLC transporters. Thus, additional knowledge about the physiological and pharmacological roles of the remaining transporter proteins is needed. Moreover, deeper insights into the reasons of individual variability in the expression and function of transporters as caused by genetic, epigenetic, and environmental factors and diseases, as well as their transcriptional and post-transcriptional regulation are required. Data on the expression and function of drug transporters in tissues beyond the most extensively studied organs, namely, liver and kidney, are also desirable to estimate the respective transporters’ function there. Finally, research on the extensive interplay between drug transporters and drug-metabolizing enzymes is so far underrepresented, although being relevant for countless drugs. The same is true for the complex interplay of uptake and efflux transporters as a physiological prerequisite for sufficient vectorial drug transport in the absorption and excretion of drugs. The latter aspect may be also interesting for transporter-based drug delivery strategies

This Special Issue aims to address some of the aforementioned open questions related to drug transporters.

Prof. Dr. Stefan Oswald
Guest Editor

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Keywords

  • drug transporters
  • ABC
  • SLC
  • variability
  • expression
  • regulation
  • function
  • genetics
  • epigenetics
  • diseases
  • interplay between metabolism and transport

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Published Papers (9 papers)

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Research

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25 pages, 6450 KiB  
Article
Use of In Vivo Imaging and Physiologically-Based Kinetic Modelling to Predict Hepatic Transporter Mediated Drug–Drug Interactions in Rats
by Nicola Melillo, Daniel Scotcher, J. Gerry Kenna, Claudia Green, Catherine D. G. Hines, Iina Laitinen, Paul D. Hockings, Kayode Ogungbenro, Ebony R. Gunwhy, Steven Sourbron, John C. Waterton, Gunnar Schuetz and Aleksandra Galetin
Pharmaceutics 2023, 15(3), 896; https://doi.org/10.3390/pharmaceutics15030896 - 10 Mar 2023
Cited by 2 | Viewed by 3585
Abstract
Gadoxetate, a magnetic resonance imaging (MRI) contrast agent, is a substrate of organic-anion-transporting polypeptide 1B1 and multidrug resistance-associated protein 2. Six drugs, with varying degrees of transporter inhibition, were used to assess gadoxetate dynamic contrast enhanced MRI biomarkers for transporter inhibition in rats. [...] Read more.
Gadoxetate, a magnetic resonance imaging (MRI) contrast agent, is a substrate of organic-anion-transporting polypeptide 1B1 and multidrug resistance-associated protein 2. Six drugs, with varying degrees of transporter inhibition, were used to assess gadoxetate dynamic contrast enhanced MRI biomarkers for transporter inhibition in rats. Prospective prediction of changes in gadoxetate systemic and liver AUC (AUCR), resulting from transporter modulation, were performed by physiologically-based pharmacokinetic (PBPK) modelling. A tracer-kinetic model was used to estimate rate constants for hepatic uptake (khe), and biliary excretion (kbh). The observed median fold-decreases in gadoxetate liver AUC were 3.8- and 1.5-fold for ciclosporin and rifampicin, respectively. Ketoconazole unexpectedly decreased systemic and liver gadoxetate AUCs; the remaining drugs investigated (asunaprevir, bosentan, and pioglitazone) caused marginal changes. Ciclosporin decreased gadoxetate khe and kbh by 3.78 and 0.09 mL/min/mL, while decreases for rifampicin were 7.20 and 0.07 mL/min/mL, respectively. The relative decrease in khe (e.g., 96% for ciclosporin) was similar to PBPK-predicted inhibition of uptake (97–98%). PBPK modelling correctly predicted changes in gadoxetate systemic AUCR, whereas underprediction of decreases in liver AUCs was evident. The current study illustrates the modelling framework and integration of liver imaging data, PBPK, and tracer-kinetic models for prospective quantification of hepatic transporter-mediated DDI in humans. Full article
(This article belongs to the Special Issue Challenges and Perspectives of Drug Transporters: Where Do We Go from Here?)
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14 pages, 1687 KiB  
Article
Transcriptional Regulation of Liver-Type OATP1B3 (Lt-OATP1B3) and Cancer-Type OATP1B3 (Ct-OATP1B3) Studied in Hepatocyte-Derived and Colon Cancer-Derived Cell Lines
by Bastian Haberkorn, Dennis Löwen, Lukas Meier, Martin F. Fromm and Jörg König
Pharmaceutics 2023, 15(3), 738; https://doi.org/10.3390/pharmaceutics15030738 - 23 Feb 2023
Cited by 1 | Viewed by 1787
Abstract
Due to alternative splicing, the SLCO1B3 gene encodes two protein variants; the hepatic uptake transporter liver-type OATP1B3 (Lt-OATP1B3) and the cancer-type OATP1B3 (Ct-OATP1B3) expressed in several cancerous tissues. There is limited information about the cell type-specific transcriptional regulation of both variants and about [...] Read more.
Due to alternative splicing, the SLCO1B3 gene encodes two protein variants; the hepatic uptake transporter liver-type OATP1B3 (Lt-OATP1B3) and the cancer-type OATP1B3 (Ct-OATP1B3) expressed in several cancerous tissues. There is limited information about the cell type-specific transcriptional regulation of both variants and about transcription factors regulating this differential expression. Therefore, we cloned DNA fragments from the promoter regions of the Lt-SLCO1B3 and the Ct-SLCO1B3 gene and investigated their luciferase activity in hepatocellular and colorectal cancer cell lines. Both promoters showed differences in their luciferase activity depending on the used cell lines. We identified the first 100 bp upstream of the transcriptional start site as the core promoter region of the Ct-SLCO1B3 gene. In silico predicted binding sites for the transcription factors ZKSCAN3, SOX9 and HNF1α localized within these fragments were further analyzed. The mutagenesis of the ZKSCAN3 binding site reduced the luciferase activity of the Ct-SLCO1B3 reporter gene construct in the colorectal cancer cell lines DLD1 and T84 to 29.9% and 14.3%, respectively. In contrast, using the liver-derived Hep3B cells, 71.6% residual activity could be measured. This indicates that the transcription factors ZKSCAN3 and SOX9 are important for the cell type-specific transcriptional regulation of the Ct-SLCO1B3 gene. Full article
(This article belongs to the Special Issue Challenges and Perspectives of Drug Transporters: Where Do We Go from Here?)
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18 pages, 2759 KiB  
Article
In Vitro and In Vivo Inhibition of MATE1 by Tyrosine Kinase Inhibitors
by Muhammad Erfan Uddin, Zahra Talebi, Sijie Chen, Yan Jin, Alice A. Gibson, Anne M. Noonan, Xiaolin Cheng, Shuiying Hu and Alex Sparreboom
Pharmaceutics 2021, 13(12), 2004; https://doi.org/10.3390/pharmaceutics13122004 - 25 Nov 2021
Cited by 10 | Viewed by 2903
Abstract
The membrane transport of many cationic prescription drugs depends on facilitated transport by organic cation transporters of which several members, including OCT2 (SLC22A2), are sensitive to inhibition by select tyrosine kinase inhibitors (TKIs). We hypothesized that TKIs may differentially interact with [...] Read more.
The membrane transport of many cationic prescription drugs depends on facilitated transport by organic cation transporters of which several members, including OCT2 (SLC22A2), are sensitive to inhibition by select tyrosine kinase inhibitors (TKIs). We hypothesized that TKIs may differentially interact with the renal transporter MATE1 (SLC47A1) and influence the elimination and toxicity of the MATE1 substrate oxaliplatin. Interactions with FDA-approved TKIs were evaluated in transfected HEK293 cells, and in vivo pharmacokinetic studies were performed in wild-type, MATE1-deficient, and OCT2/MATE1-deficient mice. Of 57 TKIs evaluated, 37 potently inhibited MATE1 function by >80% through a non-competitive, reversible, substrate-independent mechanism. The urinary excretion of oxaliplatin was reduced by about 2-fold in mice with a deficiency of MATE1 or both OCT2 and MATE1 (p < 0.05), without impacting markers of acute renal injury. In addition, genetic or pharmacological inhibition of MATE1 did not significantly alter plasma levels of oxaliplatin, suggesting that MATE1 inhibitors are unlikely to influence the safety or drug-drug interaction liability of oxaliplatin-based chemotherapy. Full article
(This article belongs to the Special Issue Challenges and Perspectives of Drug Transporters: Where Do We Go from Here?)
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17 pages, 1667 KiB  
Article
ABCB1 and ABCG2 Control Brain Accumulation and Intestinal Disposition of the Novel ROS1/TRK/ALK Inhibitor Repotrectinib, While OATP1A/1B, ABCG2, and CYP3A Limit Its Oral Availability
by Wenlong Li, Rolf W. Sparidans, Maria C. Lebre, Jos H. Beijnen and Alfred H. Schinkel
Pharmaceutics 2021, 13(11), 1761; https://doi.org/10.3390/pharmaceutics13111761 - 21 Oct 2021
Cited by 8 | Viewed by 2699
Abstract
Repotrectinib shows high activity against ROS1/TRK/ALK fusion-positive cancers in preclinical studies. We explored the roles of multidrug efflux transporters ABCB1 and ABCG2, the OATP1A/1B uptake transporter(s), and the CYP3A complex in pharmacokinetics and tissue distribution of repotrectinib in genetically modified mouse models. In [...] Read more.
Repotrectinib shows high activity against ROS1/TRK/ALK fusion-positive cancers in preclinical studies. We explored the roles of multidrug efflux transporters ABCB1 and ABCG2, the OATP1A/1B uptake transporter(s), and the CYP3A complex in pharmacokinetics and tissue distribution of repotrectinib in genetically modified mouse models. In vitro, human ABCB1 and ABCG2, and mouse Abcg2 efficiently transported repotrectinib with efflux transport ratios of 13.5, 5.6, and 40, respectively. Oral repotrectinib (10 mg/kg) showed higher plasma exposures in Abcg2-deficient mouse strains. Brain-to-plasma ratios were increased in Abcb1a/1b−/− (4.1-fold) and Abcb1a/1b;Abcg2−/− (14.2-fold) compared to wild-type mice, but not in single Abcg2−/− mice. Small intestinal content recovery of repotrectinib was decreased 4.9-fold in Abcb1a/1b−/− and 13.6-fold in Abcb1a/1b;Abcg2−/− mice. Intriguingly, Abcb1a/1b;Abcg2−/− mice displayed transient, mild, likely CNS-localized toxicity. Oatp1a/1b deficiency caused a 2.3-fold increased oral availability and corresponding decrease in liver distribution of repotrectinib. In Cyp3a−/− mice, repotrectinib plasma AUC0–h was 2.3-fold increased, and subsequently reduced 2.0-fold in humanized CYP3A4 transgenic mice. Collectively, Abcb1 and Abcg2 restrict repotrectinib brain accumulation and possibly toxicity, and control its intestinal disposition. Abcg2 also limits repotrectinib oral availability. Oatp1a/1b mediates repotrectinib liver uptake, thus reducing its systemic exposure. Systemic exposure of repotrectinib is also substantially limited by CYP3A activity. These insights may be useful to optimize the therapeutic application of repotrectinib. Full article
(This article belongs to the Special Issue Challenges and Perspectives of Drug Transporters: Where Do We Go from Here?)
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13 pages, 2156 KiB  
Article
Assessing the Functional Redundancy between P-gp and BCRP in Controlling the Brain Distribution and Biliary Excretion of Dual Substrates with PET Imaging in Mice
by Irene Hernández-Lozano, Severin Mairinger, Alexander Traxl, Michael Sauberer, Thomas Filip, Johann Stanek, Claudia Kuntner, Thomas Wanek and Oliver Langer
Pharmaceutics 2021, 13(8), 1286; https://doi.org/10.3390/pharmaceutics13081286 - 18 Aug 2021
Cited by 7 | Viewed by 2487
Abstract
P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are co-localized at the blood–brain barrier, where they display functional redundancy to restrict the brain distribution of dual P-gp/BCRP substrate drugs. We used positron emission tomography (PET) with the metabolically stable P-gp/BCRP substrates [11 [...] Read more.
P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are co-localized at the blood–brain barrier, where they display functional redundancy to restrict the brain distribution of dual P-gp/BCRP substrate drugs. We used positron emission tomography (PET) with the metabolically stable P-gp/BCRP substrates [11C]tariquidar, [11C]erlotinib, and [11C]elacridar to assess whether a similar functional redundancy as at the BBB exists in the liver, where both transporters mediate the biliary excretion of drugs. Wild-type, Abcb1a/b(−/−), Abcg2(−/−), and Abcb1a/b(−/−)Abcg2(−/−) mice underwent dynamic whole-body PET scans after i.v. injection of either [11C]tariquidar, [11C]erlotinib, or [11C]elacridar. Brain uptake of all three radiotracers was markedly higher in Abcb1a/b(−/−)Abcg2(−/−) mice than in wild-type mice, while only moderately changed in Abcb1a/b(−/−) and Abcg2(−/−) mice. The transfer of radioactivity from liver to excreted bile was significantly lower in Abcb1a/b(−/−)Abcg2(−/−) mice and almost unchanged in Abcb1a/b(−/−) and Abcg2(−/−) mice (with the exception of [11C]erlotinib, for which biliary excretion was also significantly reduced in Abcg2(−/−) mice). Our data provide evidence for redundancy between P-gp and BCRP in controlling both the brain distribution and biliary excretion of dual P-gp/BCRP substrates and highlight the utility of PET as an upcoming tool to assess the effect of transporters on drug disposition at a whole-body level. Full article
(This article belongs to the Special Issue Challenges and Perspectives of Drug Transporters: Where Do We Go from Here?)
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12 pages, 2362 KiB  
Article
Meta-Analysis of Food Effect on Oral Absorption of Efflux Transporter Substrate Drugs: Does Delayed Gastric Emptying Influence Drug Transport Kinetics?
by Sheena Sharma and Bhagwat Prasad
Pharmaceutics 2021, 13(7), 1035; https://doi.org/10.3390/pharmaceutics13071035 - 7 Jul 2021
Cited by 11 | Viewed by 4687
Abstract
The oral route of drug administration is the most convenient method of drug delivery, but it is associated with variable bioavailability. Food is one of the major factors that affect oral drug absorption by influencing drug properties (e.g., solubility and dissolution rate) and [...] Read more.
The oral route of drug administration is the most convenient method of drug delivery, but it is associated with variable bioavailability. Food is one of the major factors that affect oral drug absorption by influencing drug properties (e.g., solubility and dissolution rate) and physiological factors (e.g., metabolism and transport across the gastrointestinal tract). The aim of this work was to investigate the effect of food on the high-affinity intestinal efflux transporter substrate drugs. We hypothesized that transport efficiency is higher in the fed state as compared to the fasted state because of the lower intestinal lumen drug concentration due to prolonged gastric emptying time. A systematic analysis of reported clinical food-effect (FE) studies on 311 drugs was performed and the association of the efflux transport efficiency was investigated on the FE magnitude, i.e., changes in maximal plasma concentration and area under the plasma concentration–time profile curve for both solubility and permeability-limited drugs. In total, 124 and 88 drugs showed positive and negative FE, respectively, whereas 99 showed no FE. As expected, the solubility-limited drugs showed positive FE, but interestingly, drugs with a high potential for efflux transport, were associated with negative FE. Moreover, a high-fat diet was associated with a higher magnitude of negative FE for high-affinity efflux transporter substrates as compared to a low-fat diet. To account for changes in drug absorption after food intake, the prolonged gastric emptying time should be considered in the physiologically based pharmacokinetic (PBPK) modeling of orally absorbed efflux transporter substrate drugs. Full article
(This article belongs to the Special Issue Challenges and Perspectives of Drug Transporters: Where Do We Go from Here?)
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12 pages, 2161 KiB  
Article
Imaging-Based Characterization of a Slco2b1(-/-) Mouse Model Using [11C]Erlotinib and [99mTc]Mebrofenin as Probe Substrates
by Solène Marie, Irene Hernández-Lozano, Louise Breuil, Charles Truillet, Shuiying Hu, Alex Sparreboom, Nicolas Tournier and Oliver Langer
Pharmaceutics 2021, 13(6), 918; https://doi.org/10.3390/pharmaceutics13060918 - 21 Jun 2021
Cited by 4 | Viewed by 2489
Abstract
Organic anion-transporting polypeptide 2B1 (OATP2B1) is co-localized with OATP1B1 and OATP1B3 in the basolateral hepatocyte membrane, where it is thought to contribute to the hepatic uptake of drugs. We characterized a novel Slco2b1(-/-) mouse model using positron emission tomography (PET) imaging with [...] Read more.
Organic anion-transporting polypeptide 2B1 (OATP2B1) is co-localized with OATP1B1 and OATP1B3 in the basolateral hepatocyte membrane, where it is thought to contribute to the hepatic uptake of drugs. We characterized a novel Slco2b1(-/-) mouse model using positron emission tomography (PET) imaging with [11C]erlotinib (a putative OATP2B1-selective substrate) and planar scintigraphic imaging with [99mTc]mebrofenin (an OATP1B1/1B3 substrate, which is not transported by OATP2B1). Dynamic 40-min scans were performed after intravenous injection of either [11C]erlotinib or [99mTc]mebrofenin in wild-type and Slco2b1(-/-) mice. A pharmacokinetic model was used to estimate the hepatic uptake clearance (CL1) and the rate constants for transfer of radioactivity from the liver to the blood (k2) and excreted bile (k3). CL1 was significantly reduced in Slco2b1(-/-) mice for both radiotracers (p < 0.05), and k2 was significantly lower (p < 0.01) in Slco2b1(-/-) mice for [11C]erlotinib, but not for [99mTc]mebrofenin. Our data support previous evidence that OATP transporters may contribute to the hepatic uptake of [11C]erlotinib. However, the decreased hepatic uptake of the OATP1B1/1B3 substrate [99mTc]mebrofenin in Slco2b1(-/-) mice questions the utility of this mouse model to assess the relative contribution of OATP2B1 to the liver uptake of drugs which are substrates of multiple OATPs. Full article
(This article belongs to the Special Issue Challenges and Perspectives of Drug Transporters: Where Do We Go from Here?)
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11 pages, 1463 KiB  
Article
Impact of Th-17 Cytokines on the Regulation of Transporters in Human Placental Explants
by Kamelia Mirdamadi, Jacinda Kwok, Ori Nevo, Howard Berger and Micheline Piquette-Miller
Pharmaceutics 2021, 13(6), 881; https://doi.org/10.3390/pharmaceutics13060881 - 15 Jun 2021
Cited by 9 | Viewed by 2549
Abstract
Activated T helper 17 (Th-17) cytokines play a role in the pathophysiology of autoimmune and infectious diseases. While these diseases affect many women of childbearing age, little is known about the effect of these cytokines on placental transporters. As several pro-inflammatory cytokines impact [...] Read more.
Activated T helper 17 (Th-17) cytokines play a role in the pathophysiology of autoimmune and infectious diseases. While these diseases affect many women of childbearing age, little is known about the effect of these cytokines on placental transporters. As several pro-inflammatory cytokines impact the expression of ABC and SLC placental transporters, we hypothesized that these transporters may be similarly altered by elevated levels of circulating Th-17 cytokines. Cultured term human villous explants were treated with IL-17A, IL-22, or IL-23, alone or in combination. Samples were analyzed using qRT-PCR and Western blotting. The mRNA expression of OATP2B1 was significantly downregulated in explants by all individual cytokines and combination treatments, while decreased protein expression was seen with IL-23 and combination (p < 0.01). Combination treatment decreased the mRNA expression of BCRP and OAT4 but increased that of OCT3 (p < 0.01). Decreased accumulation of the OATP substrate, cascade blue, was seen in IL-23-treated choriocarcinoma JAr cells (p < 0.01). Elevated Th-17 cytokines, which are seen in infectious and autoimmune diseases, affect the expression and activity of OATP2B1, as well as mRNA expression of placental BCRP, OAT4, and OCT3. This dysregulation could impact the fetal exposure to endogenous and exogenous substrates. Full article
(This article belongs to the Special Issue Challenges and Perspectives of Drug Transporters: Where Do We Go from Here?)
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Review

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27 pages, 1941 KiB  
Review
Transporter Regulation in Critical Protective Barriers: Focus on Brain and Placenta
by Valerio Taggi, Mario Riera Romo, Micheline Piquette-Miller, Henriette E. Meyer zu Schwabedissen and Sibylle Neuhoff
Pharmaceutics 2022, 14(7), 1376; https://doi.org/10.3390/pharmaceutics14071376 - 29 Jun 2022
Cited by 14 | Viewed by 2998
Abstract
Drug transporters play an important role in the maintenance of chemical balance and homeostasis in different tissues. In addition to their physiological functions, they are crucial for the absorption, distribution, and elimination of many clinically important drugs, thereby impacting therapeutic efficacy and toxicity. [...] Read more.
Drug transporters play an important role in the maintenance of chemical balance and homeostasis in different tissues. In addition to their physiological functions, they are crucial for the absorption, distribution, and elimination of many clinically important drugs, thereby impacting therapeutic efficacy and toxicity. Increasing evidence has demonstrated that infectious, metabolic, inflammatory, and neurodegenerative diseases alter the expression and function of drug transporters. However, the current knowledge on transporter regulation in critical protective barriers, such as the brain and placenta, is still limited and requires more research. For instance, while many studies have examined P-glycoprotein, it is evident that research on the regulation of highly expressed transporters in the blood–brain barrier and blood–placental barrier are lacking. The aim of this review is to summarize the currently available literature in order to better understand transporter regulation in these critical barriers. Full article
(This article belongs to the Special Issue Challenges and Perspectives of Drug Transporters: Where Do We Go from Here?)
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