Interactions Between Organic Anions on Multiple Transporters in Caco-2 Cells

Grandvuinet, Anne Sophie; Steffansen, Bente

doi:10.1002/jps.22632

Cited by 14 publications

(15 citation statements)

References 52 publications

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“…OATP1A2, OATP1B1, OATP1B3, and OATP2B1 have been shown to mediate the uptake of rosuvastatin (Ho et al, 2006;Varma et al, 2011). The heteromeric OST␣-OST␤, identified as a major basolateral bile acid and steroid transporter in human intestinal epithelia (Ballatori et al, 2005), is the only basolateral exchanger known to transport organic anions (Grandvuinet and Steffansen, 2011). Thus, through the use of real-time PCR, we determined the mRNA expression levels in Caco-2 cells of the transporters commonly associated with the transport of organic anionic molecules.…”

Section: Resultsmentioning

confidence: 99%

“…Because drug transport studies with Caco-2 cells mostly focus on apical transporters, the mechanism of drug translocation across the basolateral membrane is largely ignored. Although a recent publication indicated that organic solute transporter ␣ (OST␣)-OST␤ may be involved in the basolateral uptake of taurocholic acid and estrone 3-sulfate in Caco-2 cells (Grandvuinet and Steffansen, 2011), the role of the basolateral transporter(s) in Caco-2 cells is not widely appreciated.…”

Section: Introductionmentioning

confidence: 99%

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The Role of a Basolateral Transporter in Rosuvastatin Transport and Its Interplay with Apical Breast Cancer Resistance Protein in Polarized Cell Monolayer Systems

Li¹,

Wang²,

Zhang³

et al. 2012

Drug Metab Dispos

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ABSTRACT:Membrane transporters can play a clinically important role in drug absorption and disposition; Caco-2 and Madin-Darby canine kidney (MDCK) cells are the most widely used in vitro models for studying the functions of these transporters and associated drug interactions. Transport studies using these cell models are mostly focused on apical transporters, whereas basolateral drug transport processes are largely ignored. However, for some hydrophilic drugs, a basolateral uptake transporter may be required for drugs to enter cells before they can interact with apical efflux transporters. The objective of this study was to evaluate potential differences in drug transport across Caco-2 and MDCK basolateral membrane that could cause discrepancy in the identification of efflux transporter substrates and to elucidate the underlying factors that may cause such differences, using rosuvastatin as a model substrate. Bidirectional transport results in Caco-2 and breast cancer resistance protein-MDCK cells demonstrated the necessity of an uptake transporter at the basolateral membrane for rosuvastatin. Kinetic study revealed saturable and nonsaturable processes for rosuvastatin uptake across the Caco-2 basolateral membrane, with the saturable process encompassing >75% of overall rosuvastatin basolateral uptake at concentrations below the K m (4.2 M). Furthermore, rosuvastatin basolateral transport exhibited cis-inhibition and trans-stimulation phenomena, indicating a facilitated diffusion mechanism. This basolateral transporter appeared to be a prerequisite for rosuvastatin and perhaps for other hydrophilic substrates to interact with apical efflux transporters. Deficit of such a basolateral transporter in certain cell models may lead to false-negative results when screening drug interactions with apical efflux transporters.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Role of a Basolateral Transporter in Rosuvastatin Transport and Its Interplay with Apical Breast Cancer Resistance Protein in Polarized Cell Monolayer Systems

Li¹,

Wang²,

Zhang³

et al. 2012

Drug Metab Dispos

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“…P-gp, MRP2, MRP4 and BCRP are located at the apical membrane of enterocytes, causing the drug efflux into the lumen and reducing, in consequence, the drug concentration within the enterocytes. These ABC efflux transporters are the major barrier to intestinal absorption of substrate drugs [ 5 , 9 , 10 , 186 , 187 , 188 , 191 , 192 , 193 , 194 , 195 , 196 ]. Moreover, the pattern of longitudinal expression of several intestinal transporters is not homogeneous along the human intestine, which may has functional implications on the preferable site of intestinal drug absorption.…”

Section: Study Models For Abc Transportersmentioning

confidence: 99%

Cellular Models and In Vitro Assays for the Screening of modulators of P-gp, MRP1 and BCRP

et al. 2017

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Adenosine triphosphate (ATP)-binding cassette (ABC) transporters are highly expressed in tumor cells, as well as in organs involved in absorption and secretion processes, mediating the ATP-dependent efflux of compounds, both endogenous substances and xenobiotics, including drugs. Their expression and activity levels are modulated by the presence of inhibitors, inducers and/or activators. In vitro, ex vivo and in vivo studies with both known and newly synthesized P-glycoprotein (P-gp) inducers and/or activators have shown the usefulness of these transport mechanisms in reducing the systemic exposure and specific tissue access of potentially harmful compounds. This article focuses on the main ABC transporters involved in multidrug resistance [P-gp, multidrug resistance-associated protein 1 (MRP1) and breast cancer resistance protein (BCRP)] expressed in tissues of toxicological relevance, such as the blood-brain barrier, cardiovascular system, liver, kidney and intestine. Moreover, it provides a review of the available cellular models, in vitro and ex vivo assays for the screening and selection of safe and specific inducers and activators of these membrane transporters. The available cellular models and in vitro assays have been proposed as high throughput and low-cost alternatives to excessive animal testing, allowing the evaluation of a large number of compounds.

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“…as observed for several P‐gp inhibitors) [206] . In addition, studies from our laboratory have demonstrated that several organic anionic compounds (including pharmaceutical drugs) interact with the basolateral membrane where transporters have been less studied [207,208] . Another approach to overcome the problem of nonspecific inhibitors is to knock down the transporter of interest by the introduction of small interfering RNA that promotes the degradation of target messenger RNA, e.g.…”

Section: The Challenge Of Deriving In‐vitro Kinetic Parameters For Thmentioning

confidence: 99%

Intestinal transporters for endogenic and pharmaceutical organic anions: the challenges of deriving in-vitro kinetic parameters for the prediction of clinically relevant drug–drug interactions

Grandvuinet

Vestergaard

Rapin³

et al. 2012

Journal of Pharmacy and Pharmacology

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Objectives This review provides an overview of intestinal human transporters for organic anions and stresses the need for standardization of the various in‐vitro methods presently employed in drug–drug interaction (DDI) investigations. Key findings Current knowledge on the intestinal expression of the apical sodium‐dependent bile acid transporter (ASBT), the breast cancer resistance protein (BCRP), the monocarboxylate transporters (MCT) 1, MCT3‐5, the multidrug resistance associated proteins (MRP) 1–6, the organic anion transporting polypetides (OATP) 2B1, 1A2, 3A1 and 4A1, and the organic solute transporter α/β (OSTα/β) has been covered along with an overview of their substrates and inhibitors. Furthermore, the many challenges in predicting clinically relevant DDIs from in‐vitro studies have been discussed with focus on intestinal transporters and the various methods for deducting in‐vitro parameters for transporters (Km/Ki/IC50, efflux ratio). The applicability of using a cut‐off value (estimated based on the intestinal drug concentration divided by the Ki or IC50) has also been considered. Summary A re‐evaluation of the current approaches for the prediction of DDIs is necessary when considering the involvement of other transporters than P‐glycoprotein. Moreover, the interplay between various processes that a drug is subject to in‐vivo such as translocation by several transporters and dissolution should be considered.

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Interactions Between Organic Anions on Multiple Transporters in Caco-2 Cells

Cited by 14 publications

References 52 publications

The Role of a Basolateral Transporter in Rosuvastatin Transport and Its Interplay with Apical Breast Cancer Resistance Protein in Polarized Cell Monolayer Systems

The Role of a Basolateral Transporter in Rosuvastatin Transport and Its Interplay with Apical Breast Cancer Resistance Protein in Polarized Cell Monolayer Systems

Cellular Models and In Vitro Assays for the Screening of modulators of P-gp, MRP1 and BCRP

Intestinal transporters for endogenic and pharmaceutical organic anions: the challenges of deriving in-vitro kinetic parameters for the prediction of clinically relevant drug–drug interactions

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