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Pharmaceutics
Special Issues
Drug Transporters in Absorption, Disposition and Elimination
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Drug Transporters in Absorption, Disposition and Elimination

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

Deadline for manuscript submissions: closed (30 April 2022) | Viewed by 22226

Special Issue Editor

Prof. Dr. Carsten Uhd Nielsen

E-Mail Website
Guest Editor
Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Campusvej 55, DK-5230 Odense M, Denmark
Interests: solute carriers; ABC transporters; drug absorption; ADME; amino acid transporters; transporter targeting

Special Issue Information

Dear Colleagues,

It has become clear that solute carriers (SLCs) and drug transporters of the ATP-binding cassette family (ABC transporters) are crucial determinants in the absorption, disposition, and elimination of many drug substances. Currently, the SLC family consists of more than 400 members, yet many of these carriers and their impact on drug substances in terms of cellular expression, cellular function, absorption, and disposition remain largely unexplored. Similarly, ABC transporters are known to reduce cellular retention and accumulation of low-permeable drug substances, yet formulation approaches to the modulation of their function to increase absorption or modulate disposition are few.

The present Special Issue seeks contributions in the field of solute carriers and ABC transporters in the areas of absorption, disposition, and elimination. Contributions addressing models and methods to study the function and expression of SLCs and ABCs in the broadest sense are also welcome.

This Special Issue will serve to capture contemporary progress in the field of drug transporters, in terms of both our fundamental understanding of them and their practical application.

Prof. Dr. Carsten Uhd Nielsen
Guest Editor

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Keywords

  • solute carriers
  • ABC transporters
  • absorption
  • disposition
  • elimination
  • drug-drug interactions
  • pre-clinical evaluation
  • cell culture models
  • assay development
  • formulation development
  • simulation

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Published Papers (5 papers)

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Research

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17 pages, 1523 KiB  
Article
IPEC-J2 rMdr1a, a New Cell Line with Functional Expression of Rat P-glycoprotein Encoded by Rat Mdr1a for Drug Screening Purposes
by Lasse Saaby, Josefine Trasborg, Mikkel A. Rasmussen, Bjørn Holst and Birger Brodin
Pharmaceutics 2020, 12(7), 673; https://doi.org/10.3390/pharmaceutics12070673 - 17 Jul 2020
Cited by 1 | Viewed by 3492
Abstract
The efflux pump P-glycoprotein (P-gp) affects drug distribution after absorption in humans and animals. P-gp is encoded by the multidrug resistance gene (MDR1) gene in humans, while rodents (the most common preclinical animal model) express the two isoforms Mdr1a and Mdr1b. Differences in [...] Read more.
The efflux pump P-glycoprotein (P-gp) affects drug distribution after absorption in humans and animals. P-gp is encoded by the multidrug resistance gene (MDR1) gene in humans, while rodents (the most common preclinical animal model) express the two isoforms Mdr1a and Mdr1b. Differences in substrate selectivity has also been reported. Our aim was to generate an in vitro cell model with tight barrier properties, expressing functional rat Mdr1a P-gp, as an in vitro tool for investigating species differences. The IPEC-J2 cell line forms extremely tight monolayers and was transfected with a plasmid carrying the rat Mdr1a gene sequence. Expression and P-gp localization at the apical membrane was demonstrated with Western blots and immunocytochemistry. Function of P-gp was shown through digoxin transport experiments in the presence and absence of the P-gp inhibitor zosuquidar. Bidirectional transport experiments across monolayers of the IPEC-J2 rMDR1a cell line and the IPEC-J2 MDR1 cell line, expressing human P-gp, showed comparable magnitude of transport in both the absorptive and efflux direction. We conclude that the newly established IPEC-J2 rMdr1a cell line, in combination with our previously established cell line IPEC-J2 MDR1, has the potential to be a strong in vitro tool to compare P-gp substrate profiles of rat and human P-gp. Full article
(This article belongs to the Special Issue Drug Transporters in Absorption, Disposition and Elimination)
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16 pages, 2932 KiB  
Article
Validation of Pharmacological Protocols for Targeted Inhibition of Canalicular MRP2 Activity in Hepatocytes Using [99mTc]mebrofenin Imaging in Rats
by Solène Marie, Irene Hernández-Lozano, Louise Breuil, Wadad Saba, Anthony Novell, Jean-Luc Gennisson, Oliver Langer, Charles Truillet and Nicolas Tournier
Pharmaceutics 2020, 12(6), 486; https://doi.org/10.3390/pharmaceutics12060486 - 27 May 2020
Cited by 8 | Viewed by 3629
Abstract
The multidrug resistance-associated protein 2 (MRP2) mediates the biliary excretion of drugs and metabolites. [99mTc]mebrofenin may be employed as a probe for hepatic MRP2 activity because its biliary excretion is predominantly mediated by this transporter. As the liver uptake of [ [...] Read more.
The multidrug resistance-associated protein 2 (MRP2) mediates the biliary excretion of drugs and metabolites. [99mTc]mebrofenin may be employed as a probe for hepatic MRP2 activity because its biliary excretion is predominantly mediated by this transporter. As the liver uptake of [99mTc]mebrofenin depends on organic anion-transporting polypeptide (OATP) activity, a safe protocol for targeted inhibition of hepatic MRP2 is needed to study the intrinsic role of each transporter system. Diltiazem (DTZ) and cyclosporin A (CsA) were first confirmed to be potent MRP2 inhibitors in vitro. Dynamic acquisitions were performed in rats (n = 5–6 per group) to assess the kinetics of [99mTc]mebrofenin in the liver, intestine and heart-blood pool after increasing doses of inhibitors. Their impact on hepatic blood flow was assessed using Doppler ultrasound (n = 4). DTZ (s.c., 10 mg/kg) and low-dose CsA (i.v., 0.01 mg/kg) selectively decreased the transfer of [99mTc]mebrofenin from the liver to the bile (k3). Higher doses of DTZ and CsA did not further decrease k3 but dose-dependently decreased the uptake (k1) and backflux (k2) rate constants between blood and liver. High dose of DTZ (i.v., 3 mg/kg) but not CsA (i.v., 5 mg/kg) significantly decreased the blood flow in the portal vein and hepatic artery. Targeted pharmacological inhibition of hepatic MRP2 activity can be achieved in vivo without impacting OATP activity and liver blood flow. Clinical studies are warranted to validate [99mTc]mebrofenin in combination with low-dose CsA as a novel substrate/inhibitor pair to untangle the role of OATP and MRP2 activity in liver diseases. Full article
(This article belongs to the Special Issue Drug Transporters in Absorption, Disposition and Elimination)
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24 pages, 2212 KiB  
Article
Acamprosate Is a Substrate of the Human Organic Anion Transporter (OAT) 1 without OAT3 Inhibitory Properties: Implications for Renal Acamprosate Secretion and Drug–Drug Interactions
by Irina E. Antonescu, Maria Karlgren, Maria L. Pedersen, Ivailo Simoff, Christel A. S. Bergström, Sibylle Neuhoff, Per Artursson, Bente Steffansen and Carsten Uhd Nielsen
Pharmaceutics 2020, 12(4), 390; https://doi.org/10.3390/pharmaceutics12040390 - 24 Apr 2020
Cited by 8 | Viewed by 4816
Abstract
Acamprosate is an anionic drug substance widely used in treating symptoms of alcohol withdrawal. It was recently shown that oral acamprosate absorption is likely due to paracellular transport. In contrast, little is known about the eliminating mechanism clearing acamprosate from the blood in [...] Read more.
Acamprosate is an anionic drug substance widely used in treating symptoms of alcohol withdrawal. It was recently shown that oral acamprosate absorption is likely due to paracellular transport. In contrast, little is known about the eliminating mechanism clearing acamprosate from the blood in the kidneys, despite the fact that studies have shown renal secretion of acamprosate. The hypothesis of the present study was therefore that renal organic anion transporters (OATs) facilitate the renal excretion of acamprosate in humans. The aim of the present study was to establish and apply OAT1 (gene product of SLC22A6) and OAT3 (gene product of SLC22A8) expressing cell lines to investigate whether acamprosate is a substrate or inhibitor of OAT1 and/or OAT3. The studies were performed in HEK293-Flp-In cells stably transfected with SLC22A6 or SLC22A8. Protein and functional data showed that the established cell lines are useful for studying OAT1- and OAT3-mediated transport in bi-laboratory studies. Acamprosate inhibited OAT1-mediated p-aminohippuric acid (PAH) uptake but did not inhibit substrate uptake via OAT3 expressing cells, neither when applied concomitantly nor after a 3 h preincubation with acamprosate. The uptake of PAH via OAT1 was inhibited in a competitive manner by acamprosate and cellular uptake studies showed that acamprosate is a substrate for OAT1 with a Km-value of approximately 700 µM. Probenecid inhibited OAT1-mediated acamprosate uptake with a Ki-value of approximately 13 µM, which may translate into an estimated clinically significant DDI index. In conclusion, acamprosate was identified as a substrate of OAT1 but not OAT3. Full article
(This article belongs to the Special Issue Drug Transporters in Absorption, Disposition and Elimination)
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Review

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20 pages, 3018 KiB  
Review
Strategies and Mechanism in Reversing Intestinal Drug Efflux in Oral Drug Delivery
by Rong Lu, Yun Zhou, Jinqian Ma, Yuchen Wang and Xiaoqing Miao
Pharmaceutics 2022, 14(6), 1131; https://doi.org/10.3390/pharmaceutics14061131 - 26 May 2022
Cited by 10 | Viewed by 3703
Abstract
Efflux transporters distributed at the apical side of human intestinal epithelial cells actively transport drugs from the enterocytes to the intestinal lumen, which could lead to extremely poor absorption of drugs by oral administration. Typical intestinal efflux transporters involved in oral drug absorption [...] Read more.
Efflux transporters distributed at the apical side of human intestinal epithelial cells actively transport drugs from the enterocytes to the intestinal lumen, which could lead to extremely poor absorption of drugs by oral administration. Typical intestinal efflux transporters involved in oral drug absorption process mainly include P-glycoprotein (P-gp), multidrug resistance proteins (MRPs) and breast cancer resistance protein (BCRP). Drug efflux is one of the most important factors resulting in poor absorption of oral drugs. Caco-2 monolayer and everted gut sac are sued to accurately measure drug efflux in vitro. To reverse intestinal drug efflux and improve absorption of oral drugs, a great deal of functional amphiphilic excipients and inhibitors with the function of suppressing efflux transporters activity are generalized in this review. In addition, different strategies of reducing intestinal drugs efflux such as silencing transporters and the application of excipients and inhibitors are introduced. Ultimately, various nano-formulations of improving oral drug absorption by inhibiting intestinal drug efflux are discussed. In conclusion, this review has significant reference for overcoming intestinal drug efflux and improving oral drug absorption. Full article
(This article belongs to the Special Issue Drug Transporters in Absorption, Disposition and Elimination)
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16 pages, 1205 KiB  
Review
Prediction of Drug-Induced Hyperbilirubinemia by In Vitro Testing
by Péter Tátrai and Péter Krajcsi
Pharmaceutics 2020, 12(8), 755; https://doi.org/10.3390/pharmaceutics12080755 - 11 Aug 2020
Cited by 13 | Viewed by 5664
Abstract
Bilirubin, the end product of heme catabolism, is produced continuously in the body and may reach toxic levels if accumulates in the serum and tissues; therefore, a highly efficient mechanism evolved for its disposition. Normally, unconjugated bilirubin enters hepatocytes through the uptake transporters [...] Read more.
Bilirubin, the end product of heme catabolism, is produced continuously in the body and may reach toxic levels if accumulates in the serum and tissues; therefore, a highly efficient mechanism evolved for its disposition. Normally, unconjugated bilirubin enters hepatocytes through the uptake transporters organic anion transporting polypeptide (OATP) 1B1 and 1B3, undergoes glucuronidation by the Phase II enzyme UDP glucuronosyltransferase 1A1 (UGT1A1), and conjugated forms are excreted into the bile by the canalicular export pump multidrug resistance protein 2 (MRP2). Any remaining conjugated bilirubin is transported back to the blood by MRP3 and passed on for uptake and excretion by downstream hepatocytes or the kidney. The bile salt export pump BSEP as the main motor of bile flow is indirectly involved in bilirubin disposition. Genetic mutations and xenobiotics that interfere with this machinery may impede bilirubin disposition and cause hyperbilirubinemia. Several pharmaceutical compounds are known to cause hyperbilirubinemia via inhibition of OATP1Bs, UGT1A1, or BSEP. Herein we briefly review the in vitro prediction methods that serve to identify drugs with a potential to induce hyperbilirubinemia. In vitro assays can be deployed early in drug development and may help to minimize late-stage attrition. Based on current evidence, drugs that behave as mono- or multispecific inhibitors of OATP1B1, UGT1A1, and BSEP in vitro are at risk of causing clinically significant hyperbilirubinemia. By integrating inhibition data from in vitro assays, drug serum concentrations, and clinical reports of hyperbilirubinemia, predictor cut-off values have been established and are provisionally suggested in this review. Further validation of in vitro readouts to clinical outcomes is expected to enhance the predictive power of these assays. Full article
(This article belongs to the Special Issue Drug Transporters in Absorption, Disposition and Elimination)
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