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Research ArticleArticle

Expression of Organic Anion Transporting Polypeptide 1A2 in Red Blood Cells and Its Potential Impact on Antimalarial Therapy

Andrea Hubeny, Markus Keiser, Stefan Oswald, Gabriele Jedlitschky, Heyo K. Kroemer, Werner Siegmund and Markus Grube
Drug Metabolism and Disposition October 2016, 44 (10) 1562-1568; DOI: https://doi.org/10.1124/dmd.116.069807
Andrea Hubeny
Department of Pharmacology (A.H., G.J., H.K.K., M.G.) and Department of Clinical Pharmacology (M.K., S.O., W.S.) at the Center of Drug Absorption and Transport (C_DAT), University Medicine, Greifswald, Germany
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Markus Keiser
Department of Pharmacology (A.H., G.J., H.K.K., M.G.) and Department of Clinical Pharmacology (M.K., S.O., W.S.) at the Center of Drug Absorption and Transport (C_DAT), University Medicine, Greifswald, Germany
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Stefan Oswald
Department of Pharmacology (A.H., G.J., H.K.K., M.G.) and Department of Clinical Pharmacology (M.K., S.O., W.S.) at the Center of Drug Absorption and Transport (C_DAT), University Medicine, Greifswald, Germany
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Gabriele Jedlitschky
Department of Pharmacology (A.H., G.J., H.K.K., M.G.) and Department of Clinical Pharmacology (M.K., S.O., W.S.) at the Center of Drug Absorption and Transport (C_DAT), University Medicine, Greifswald, Germany
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Heyo K. Kroemer
Department of Pharmacology (A.H., G.J., H.K.K., M.G.) and Department of Clinical Pharmacology (M.K., S.O., W.S.) at the Center of Drug Absorption and Transport (C_DAT), University Medicine, Greifswald, Germany
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Werner Siegmund
Department of Pharmacology (A.H., G.J., H.K.K., M.G.) and Department of Clinical Pharmacology (M.K., S.O., W.S.) at the Center of Drug Absorption and Transport (C_DAT), University Medicine, Greifswald, Germany
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Markus Grube
Department of Pharmacology (A.H., G.J., H.K.K., M.G.) and Department of Clinical Pharmacology (M.K., S.O., W.S.) at the Center of Drug Absorption and Transport (C_DAT), University Medicine, Greifswald, Germany
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Abstract

Important antimalarial drugs, including quinolines, act against blood schizonts by interfering with hemoglobin metabolism. To reach their site of action, these compounds have to cross the plasma membrane of red blood cells (RBCs). Organic cation transporters (OCTs) and organic anion transporting polypeptides (OATPs) are important uptake transporters and interesting candidates for local drug transport. We therefore studied their interaction with antimalarial compounds (quinine, chloroquine, mefloquine, pyrimethamine, artemisinin, and artesunate) and characterized the expression of OATP1A2 and OATP2B1 in RBCs. Competition assays using transporter-overexpressing Madin-Darby canine kidney (MDCKII) cells and the model substrate estrone-3-sulfate identified quinine and chloroquine as potent inhibitors of OATP1A2 function (IC50 quinine: 0.7 ± 1.2 µM; chloroquine: 1.0 ± 1.5 µM), but no or only moderate effects were observed for OATP2B1. Subsequently, quinine was identified as a substrate of OATP1A2 (Km 23.4 µM). The OATP1A2-mediated uptake was sensitive to the OATP1A2-specific inhibitor naringin. Both OATPs were expressed in human RBCs, and ex vivo transport studies demonstrated naringin-sensitive accumulation of quinine in these cells (60 pmol versus 38 pmol/5 × 105 RBCs). Additional transport studies using OCT1–3 and organic cation transporter novel type 1 (OCTN1) indicated only significant quinine uptake by OCT1, which was not detected in RBCs. In conclusion, our data demonstrate expression of OATP2B1 and OATP1A2 in RBCs as well as OATP1A2-mediated uptake of quinine. Therefore, modulation of OATP1A2 function may affect quinine uptake into erythrocytes.

Introduction

Malaria remains one of the world’s most important infectious diseases, with 214 million new cases and 438,000 deaths in 2015 (WHO, 2015). For treatment of malaria, only a limited number of effective drugs are available. To prevent replication of blood-stage malaria parasites, quinoline-based drugs, such as quinine and chloroquine, that inhibit heme detoxification in the food vacuole are widely used (Kumar et al., 2007). Thus, to reach their intracellular target structures, these compounds have to cross the erythrocyte membrane. For a wide variety of drugs, including several antimalarial compounds, drug transporters of the ATP-binding cassette (ABC), solute carrier (SLC), or solute carrier organic anion (SLCO) family are involved in transmembrane transfer (Konig et al., 2013). For example, mefloquine, quinine, and chloroquine are inhibitors or substrates of efflux pumps such as P-glycoprotein (P-gp/ABCB1) (Riffkin et al., 1996; Pham et al., 2000; Rijpma et al., 2014), multidrug-resistance protein 1 (MRP1, ABCC1) and multidrug-resistance protein 4 (MRP4, ABCC4) (Wu et al., 2005), and chloroquine and quinine have been identified as inhibitors and substrates of multidrug and toxin extrusion protein 1 (MATE1, SLC47A1) and organic cation transporters (OCTs) (Muller et al., 2011; Nies et al., 2012). In addition, there is evidence that quinine interacts with organic anion transporting polypeptides (OATPs), in particular OATP1A2, which has been shown to transport N-methyl-quinine (Kullak-Ublick et al., 2001; Shitara et al., 2002).

Interestingly, the impact of OATPs has not been addressed in detail in this context. Among the 11 human OATP transporters, OATP1B1, OATP1B3, OATP2B1, and OATP1A2 are of the most pharmacologic relevance. OATP1B1 and OATP1B3 are predominantly, or even exclusively, expressed in the liver, but OATP1A2 and OATP2B1 show broad expression profiles. Thus, OATP1A2 and OATP2B1 are especially interesting candidates for local drug distribution (Konig et al., 2013).

We therefore characterized the expression of OATP1A2 and OATP2B1 in red blood cells (RBCs) and studied the interaction of antimalarial drugs with these transporters in comparison with the organic cation transporters OCT1, OCT2, OCT3, and organic cation transporter novel type 1 (OCTN1). Thus, we were able to demonstrate expression of OATP1A2 and OATP2B1 in RBCs and identified OATP1A2 as an uptake transporter for quinine in these cells.

Materials and Methods

Materials.

Radiolabeled tracer compounds [3H]estrone-3-sulfate ([3H]E1S, 50 Ci/mmol), [3H]1-methyl-4-phenylpyridinium ([3H]MPP+, 80 Ci/mmol), [14C]tetraethylammonium ([14C]TEA, 55 mCi/mmol), and [3H]quinine (20 Ci/mmol) were obtained from Hartmann Analytic (Braunschweig, Germany). Antimalarial compounds were purchased from Sigma-Aldrich (Steinheim, Germany).

Cell Culture.

Madin-Darby canine kidney (MDCKII) cells overexpressing human OATP2B1 or OCT were described previously elsewhere (Grube et al., 2006, 2011). OATP1A2-overexpressing MDCKII cells were generated as described elsewhere for transporter-overexpressing human embryonic kidney 293 (HEK293) cells (Leonhardt et al., 2010). The cells were grown in 75 cm2 cell culture flasks in Dulbecco’s modified Eagle’s medium supplemented with 2 mM l-glutamine, 1% minimal essential medium nonessential amino acids, 10% fetal calf serum, 100 U/ml penicillin, and 100 µg/ml streptomycin at 37°C in a humidified atmosphere containing 5% CO2. Except for the experiments, transfected cell lines were cultured in selection medium containing neomycin 0.5 mg/ml (OATP1A2), hygromycin B 350 µg/ml (OATP2B1, OCT3), or blasticidin 10 µg/ml (OCT1–2).

Preparation of Red Blood Cells.

After approval by the local ethics committee of the University Medicine Greifswald, blood samples were taken from male and female healthy volunteers. RBCs were prepared from fresh, EDTA-treated venous blood by layering on Mono-Poly Resolving Medium (MP Biomedicals, Eschwege, Germany) with subsequent centrifugation at 300g for 30 minutes. The resulting pellet of RBCs was washed with isotonic phosphate-buffered saline (PBS) solution and immediately used for transport studies or stored at −80°C for immunoblotting.

Immunofluorescence Staining.

Protein localization in transfected MDCKII cells was studied as described elsewhere for transporter-overexpressing human embryonic kidney 293 (HEK293) cells (Grube et al., 2006; Leonhardt et al., 2010; Mandery et al., 2010). For detection of OCT, the cells were fixed with ethanol (70% or 99%) for 10 minutes at room temperature, permeabilized with 0.4% Tween-20 in PBS, and blocked using 5% fetal calf serum in PBS. OCT1 was detected using the antibody ab123128 (rabbit, 1/25; Abcam, Cambridge, United Kingdom). For OCT2 detection the antibody HPA008567 (rabbit, 1/25 dilution; Sigma-Aldrich) was used; OCT3 was detected by C-14 (goat, 1/50 dilution; Santa Cruz Biotechnology, Heidelberg, Germany), and OCTN1 by A01 (mouse, 1/25 dilution; Abnova, Taipei City, Taiwan).

Localization of OATP1A2 and OATP2B1 in human RBCs was also characterized by immunofluorescence staining. EDTA-treated whole blood smears were fixed with methanol (OATP1A2, room temperature) or acetone (OATP2B1, −20°C) for 10 minutes, permeabilized with 0.4% Tween-20 in PBS for 10 minutes, and blocked using 5% fetal calf serum in PBS. OATP1A2 was detected using the polyclonal antibody C18884 (rabbit, 1/20 dilution; Assay Biotechnology, Sunnyvale, CA). OATP2B1 detection was performed using transporter-specific rabbit antiserum (1/200 dilution; Grube et al., 2005). RBCs were additionally stained with phycoerythrin-labeled CD235a (1/200 dilution; BD Pharmingen, Heidelberg, Germany). All immunofluorescence stainings were analyzed using the LSM780 confocal laser scanning system (Carl Zeiss MicroImaging, Jena, Germany). Only signals above the background fluorescence determined by control stainings using preimmune serum (rabbit) were shown.

Immunoblot Analysis.

Membrane fractions of MDCKII cells and RBCs were separated by a 7.5% sodium dodecyl sulfate (SDS) polyacrylamide gel after denaturation at 95°C for 5 minutes. Immunoblotting was performed using a tank blotting system (Bio-Rad Laboratories, Munich, Germany). Primary antibodies were diluted in Tris-buffered saline containing 0.05% Tween-20 and 0.1% bovine serum albumin to the following final concentration: OATP1A2 antibody (C18884, 1/2000; Assay Biotechnology) and OATP2B1 antibody (1/1000); secondary horseradish peroxidase-conjugated goat anti-rabbit IgG antibody (Bio-Rad Laboratories) was used at a 1/2000 dilution. Detection was performed using the enhanced chemiluminescence detection system (Thermo Scientific, Schwerte, Germany).

Transport Assays.

For functional experiments in the transporter overexpressing MDCKII cells, radiolabeled transporter substrates (E1S: OAT1A2 and OATP2B1; MPP+: OCT1, OCT2, and OCT3; TEA: OCTN1) were used. Cells (70,000 cells/well) were cultured in 24-well plates for 4 days. One day before the experiment, the medium was changed, and the cells were incubated with 2.5 mM sodium butyrate to stimulate transporter expression.

For inhibition studies, the cells were washed once with prewarmed PBS and incubated at 37°C with transport buffer containing the radiolabeled substrate and the test compound. After 5 minutes, substrate uptake was stopped by aspiration of incubation buffer and washing 3 times with ice-cold PBS.

Cells were lysed with 800 µl 0.2% SDS and 5 mM EDTA, and an aliquot of 200 µl was dissolved in 2 ml of scintillation mixture (Rotiszint Eco Plus, Roth, Karlsruhe, Germany). Radioactivity was measured in a scintillation β-counter (type 1409; LKB-Wallac/PerkinElmer, Freiburg, Germany). For normalization, the protein concentration of the whole-cell lysate was determined using the BCA method (Thermo Scientific, Waltham, MA).

Quinine uptake experiments were performed in transporter-overexpressing and control MDCKII cells for the indicated time points using tritium-labeled quinine and the OATP1A2 inhibitor naringin (100 µM) (Bailey, 2010). Quinine uptake into RBCs was studied by a rapid filtration method using polyvinylidene difluoride (0.2 µm pore size) filter membranes. We suspended 5 × 105 RBCs in prewarmed transport buffer, then incubated them with quinine in the presence or absence of naringin (100 µM) for 30 minutes at 37°C and 4°C, respectively. The reaction was stopped by adding 1 ml of ice-cold PBS containing naringin (100 µM). RBC samples were filtered immediately through a polyvinylidene difluoride filter (presoaked in PBS containing 100 µM naringin) and rinsed 3 times with 3 ml of ice-cold PBS. For measurement of radioactivity, the filter was dissolved in 5 ml of scintillation mixture (Rotiszint; Roth) and measured as described earlier.

All transport studies were performed with incubation/transport buffer containing 140 mM NaCl2, 5 mM KCl, 1 mM KH2PO4, 1.5 mM CaCl2, 5 mM glucose, and 12.5 mM HEPES (pH 7.3). For pH 6.0 studies, the pH of the incubation buffer was adjusted using HCl.

Statistical Methods.

For calculations, graphs, and statistical analyses, we used Excel (Microsoft Corp., Redmond, WA) and GraphPad Prism 5.01 (GraphPad, San Diego, CA). Competition experiments were calculated as the percentage of transporter-overexpressing MDCKII cells treated with vehicle. The IC50 values were determined by nonlinear regression from sigmoidal dose–response curves using the following constraints: top = 0% inhibition and bottom ≤100% inhibition. To determine statistical significance, one-way or two-way analysis of variance followed by Dunnett’s or Tukey’s multiple comparison test were used for analyzing multiple groups. P < 0.05 was considered statistically significant.

Results

Using transporter-overexpressing MDCKII cells and the probe substrates E1S (1 µM) for OATP1A2 and OATP2B1, MPP+ (500 nM) for the OCTs, and TEA (0.3 µM) for OCTN1, the interactions between the antimalarial drugs quinine, chloroquine, mefloquine, pyrimethamine, artemisinin, and artesunate and the individual transporters were studied. Transporter overexpression was confirmed by immunofluorescence staining, demonstrating a basolateral localization for OATP2B1 and the OCT(N)s, while OATP1A2 was localized to the apical membrane (Fig. 1; Supplemental Fig. 1). Functional studies in transporter-overexpressing and vector-transfected MDCKII cells revealed transporter-specific uptake of the respective probe substrates (Fig. 1).

Fig. 1.
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Fig. 1.

Interaction between OATP and OCT(N) transporters and antimalarial compounds. E1S (1 µM, 5 minutes, OATP1A2, OATP2B1), MPP+ (0.5 µM, 1.5 minutes, OCT1–3) and TEA (0.3 µM, 5 minutes, OCTN1) uptake was studied in transporter-overexpressing MDCKII cells in the presence and absence of the respective compound (each 100 µM) as well as in vector-transfected control cells (MDCKII). Data are represented in relation to transporter-overexpressing cells (100%, dotted line), mean+ S.D., n = 2–4, one-way analysis of variance and Dunnett’s multiple comparison test versus control-treated MDCKII-OATP1A2 cells; *P < 0.05, **P < 0.01, ***P < 0.001. Inserts: Immunofluorescence staining of respective transporter (bars: 20 µm).

In competition studies, all the compounds with the exception of artesunate (100 µM each) showed inhibition of OATP1A2-, OCT1-, and OCT2-mediated transport. OATP2B1 function was only slightly affected by mefloquine, but OCT3 and OCTN1 were not inhibited by any of the antimalarial drugs (Fig. 1).

The most potent interactions were further characterized by determination of the respective half-maximal inhibitory concentrations (IC50 values), identifying quinine and chloroquine as higher affinity inhibitors of OATP1A2 (IC50 quinine: 0.7 ± 1.2 µM; chloroquine: 1.0 ± 1.5 µM) compared with mefloquine (IC50 6.0 ± 3.4 µM) (Fig. 2). The respective IC50 values for OCT1 and/or OCT2 were higher than those for OATP1A2, but also in low micromolar range (Table 1).

Fig. 2.
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Fig. 2.

Determination of half-maximal inhibitory concentrations (IC50 values) of quinine, chloroquine, and mefloquine for OATP1A2-mediated E1S transport (1 µM, 5 minutes). Data represent the background corrected mean values (mean ± S.D., n = 3–4).

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TABLE 1

Half-maximal inhibitory concentrations (IC50 values) and maximal inhibitory effects of selected antimalarial compounds for OATP1A2, OCT1, and OCT2

Data represent background corrected IC50 values (mean ± S.D.) from three to four experiments.

Subsequently, we examined the direct uptake of quinine, the most potent inhibitor. Although no OATP2B1-mediated transport was observed, OATP1A2-overexpressing cells displayed time-dependent accumulation of quinine, compared with the vector-transfected MDCKII cells (Fig. 3A). The total quinine uptake was pH-sensitive, with higher uptake rates at pH 7.3 compared with pH 6.0, whereas the OATP1A2-specific uptake rate was comparable at both pH values (Fig. 3B). In addition, OATP1A2-mediated quinine uptake was sensitive to the OATP1A2-specific inhibitor naringin at both pH 7.3 and pH 6.0 (Fig. 3C). The kinetic parameters of the OATP1A2-mediated quinine transport were 23.4 ± 6.1 µM for Km, and 241 ± 24 pmol/mg/min for Vmax (Fig. 3D).

Fig. 3.
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Fig. 3.

Quinine uptake into transporter-overexpressing MDCKII cells. (A) Time-dependent quinine uptake (1 µM) at pH 7.3 into OATP1A2- and OATP2B1-overexpressing MDCKII cells (mean ± S.D., n = 3–4). (B) OATP1A2-mediated quinine uptake (1 µM) at pH 7.3 and pH 6.0 (hatched columns) (mean ± S.D., n = 3, two-way analysis of variance and Tukey’s multiple comparison test, *P < 0.05, **P < 0.01, ***P < 0.001). (C) Sensitivity of OATP1A2-mediated quinine uptake (1 µM, 30 minutes) to the OATP1A2 inhibitor naringin (100 µM) at pH 7.3 and pH 6.0 (mean ± S.D., n = 3, one-way analysis of variance and Tukey’s multiple comparison test, *P < 0.05, **P < 0.01). (D) Concentration-dependent uptake of quinine (0.78–100 µM, 5 minutes) at pH 7.3 by OATP1A2. OATP1A2-specific transport was used to calculate kinetic parameters (mean ± S.D., n = 6).

Quinine uptake by OCT1 and OCT2 was also studied. Slight, but significant, quinine uptake was observed only for OCT1 (Supplemental Fig. 2A). However, OCT1 function was not affected by naringin, as shown by using the standard OCT1 substrate MPP+ (Supplemental Fig. 2B).

Transporter expression was analyzed in RBCs by use of immunofluorescence microscopy. OATP1A2 and OATP2B1 were expressed in the membrane of human RBCs and colocalized with the erythrocyte surface marker CD235a (Fig. 4A). Concerning the organic cation transporters, no signal was detected for OCT1–3 (data not shown) whereas OCTN1 was localized to the plasma membrane (Supplemental Fig. 3A).

Fig. 4.
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Fig. 4.

(A) Immunofluorescence staining of OATP1A2 and OATP2B1 in RBC. Whole-blood smears were probed against OATP1A2 and OATP2B1 (both green). Costaining was performed with the erythrocyte membrane marker CD235a (red). Control stainings with preimmune serum exhibited no specific signals (inserts). Scale bar: 5 µm. (B) Immunoblot of crude membrane fractions of RBC and transporter-overexpressing MDCKII cells (control) using OATP-specific antibodies. (C) In vitro uptake of quinine (100 nM) into RBCs measured at 37°C and 4°C in the presence and absence of the OATP1A2 inhibitor naringin (100 µM) (mean ± S.D., n = 4 RBC preparations, one-way analysis of variance and Tukey’s multiple comparison test, *P < 0.05, **P < 0.01).

For the OATPs as well as OCTN1 these findings were verified by Western blot analysis, demonstrating transporter-specific signals at the expected molecular masses (OATP2B1 ∼84 kDa; OATP1A2∼74 kDa; OCTN1 ∼62 kDa, Fig. 4B; Supplemental Fig. 3B). Finally, quinine uptake into RBCs was studied ex vivo using erythrocytes from healthy volunteers. Significant temperature-dependent transport was observed (60 ± 10 pmol/5 × 105 RBCs at 37°C versus 34 ± 7 pmol/5 × 105 RBCs at 4°C), which was inhibited by the OATP1A2-inhibitor naringin (100 µM) at 37°C, but not at 4°C (Fig. 4C).

Discussion

In the present study, we were able to show interactions between antimalarial drugs and OATPs as well as identified quinine as a substrate of OATP1A2. In addition, we demonstrated expression of OATP2B1 and OATP1A2 in erythrocytes.

To reach their target sites, antimalarial drugs have to cross the erythrocyte plasma membrane. OATPs, especially OATP1A2 and OATP2B1, are interesting candidates for local drug uptake into RBCs (Konig et al., 2013). We therefore characterized the interaction of both transporters with antimalarial drugs acting against blood schizonts (quinine, chloroquine, mefloquine, pyrimethamine, artemisinin, and artesunate) using transporter-overexpressing MDCKII cells in addition to studying transporter expression in RBCs. Transporter expression and function were shown for each transporter-overexpressing cell line. Of note, in contrast to other OATPs, OATP1A2 was localized in the apical membrane of MDCKII cells. This finding was in line with a recent study using a similar model (Liu et al., 2015) and corresponds to the physiologic localization of this transporter in tissues such as the blood–brain barrier (Bronger et al., 2005) or the kidney (Lee et al., 2005).

Using these systems, interaction studies between antimalarial drugs and OATP1A2 and OATP2B1 revealed no significant influence on OATP2B1 function. OATP1A2 was inhibited by almost all tested compounds (except artesunate). Among them, chloroquine and quinine were identified as the most potent inhibitors, although the maximal inhibitory effect for chloroquine was much lower compared with quinine.

Half-maximal inhibitory concentrations of 1.0 and 0.7 µM were calculated for chloroquine and quinine, respectively. These findings are in line with the results of a very recent study on the interaction between chloroquine and OATP1A2 (Xu et al., 2016). Compared with therapeutic concentrations, this value is only slightly above the plasma concentration of chloroquine (300–600 nM) (Muller et al., 2011) and even an order of magnitude below the levels reached in quinine therapy (6–25 µM) (Powell and McNamara, 1972; Hall et al., 1973). Hence, coapplication of chloroquine or quinine with other OATP1A2 substrates might lead to drug–drug interactions at the transporter level.

The impact of OATP1A2 in drug absorption and systemic bioavailability is still a controversial issue (Glaeser et al., 2007; Groer et al., 2013), but its luminal localization in the blood–brain barrier points to an important function for distribution processes into the brain (Cheng et al., 2012). Therefore, antimalarial therapy using chloroquine or quinine may interfere with OATP1A2 substrates such as neurosteroids (Gao et al., 2015) and opioid peptides (Gao et al., 2000), and drugs such as triptans (Cheng et al., 2012).

Besides its inhibitory function, quinine was shown to be a substrate of OATP1A2 with an affinity in the low micromolar range. This finding was in line with a previous report demonstrating OATP1A2-mediated uptake of the closely related N-methyl-quinine (Kullak-Ublick et al., 2001). The transport of other OATP1A2 substrates such as E1S or methotrexate is enhanced at lower pH (Badagnani et al., 2006; Leuthold et al., 2009), but the total uptake of quinine was reduced at pH 6.0, most likely due to reduced passive diffusion caused by an increase in the fraction of ionized molecule (pKa 8.15–8.58). In addition, quinine is another example of an OATP1A2 substrate with cationic character, such as trospium chloride (Bexten et al., 2015) or rocuronium (van Montfoort et al., 2001), indicating a more amphiphilic substrate spectrum of OATP1A2 compared with other OATPs.

Malaria is the most important therapeutic indication for quinine. Here, it acts against blood schizonts by inhibition of heme detoxification, resulting in free cytotoxic heme, which accumulates and kills the parasite. Quinine rapidly enters the erythrocyte; however, intracellular concentrations are below the corresponding plasma levels, indicating transporter proteins are involved in quinine distribution (Salako and Sowunmi, 1992). It is well established that quinine is transported by P-gp, thereby limiting the neurotoxic side effects of the drug (Kerb et al., 2009). However, P-gp expression in erythrocytes is very low (Abraham et al., 2001), so the presence of a saturable quinine uptake transporter in RBCs may also help to explain this observation.

We were able to show the expression of OATP2B1 and OATP1A2 in the plasma membrane of erythrocytes, pointing to a possible role for OATP1A2 in quinine uptake from the blood plasma to the target site. This hypothesis was confirmed by our in vitro results demonstrating temperature-dependent and naringin-sensitive uptake of quinine into human erythrocytes. As a consequence of this finding, the concomitant therapy of quinine and other OATP1A2 substrates and/or inhibitors may interfere with quinine distribution and action. Indeed, there is evidence for an interaction between quinine and the OATP1A2 inhibitor ritonavir, which has been shown to significantly increase quinine Cmax and the area under the curve (Cvetkovic et al., 1999; Soyinka et al., 2010). Although those investigators attributed this observation to the inhibition of quinine metabolism via CYP3A4 by ritonavir, it is likewise possible that transporters are involved.

Ritonavir is also known as a potent inhibitor of P-gp (Lee et al., 1998). However, because quinine is well absorbed in the gut with a bioavailability above 80%, inhibition of intestinal P-gp is unlikely to be the reason for the observed increase in the plasma levels (Paintaud et al., 1993; Soyinka et al., 2010). Inhibition of P-gp in RBCs would result in the opposite effect, but inhibition of OATP1A2 uptake into the erythrocytes could also contribute to increased drug levels in the plasma.

Moreover, not only may drug–drug interactions influence quinine uptake into RBCs, but also genetic polymorphisms or environmental factors may have an effect. For example, genetic variants in the SLCO1A2 gene encoding OATP1A2, as well as several food components, including fruit juices, green tea, and the flavonoid quercetin, have been shown to affect OATP1A2 function (Bailey, 2010; Mandery et al., 2010; Yamakawa et al., 2011; Misaka et al., 2014).

These results indicate an involvement of OATP1A2 for quinine uptake into RBCs, but the possible impact of other transporters must also be taken in account. According to its cationic character, members of the OCT family are especially interesting candidates. Indeed, we were able to show inhibition of OCT1- and OCT2-mediated MPP+ uptake by quinine, and direct transport of quinine by OCT1, which was in line with previous reports (Arndt et al., 2001; Koepsell et al., 2007). Although quinine transport by OCT1 might be relevant for the hepatic uptake and in turn the metabolism of quinine (Kerb et al., 2009), we were not able to detect OCT1 in erythrocytes, and OCT1 function was not affected by naringin.

Another possible candidate for quinine uptake into RBCs is OCTN1. This transporter is expressed in erythrocytes (Kobayashi et al., 2004), is inhibited by quinine, and has been shown to transport the quinine diastereomer quinidine (Yabuuchi et al., 1999). However, in contrast to these previous reports, we could not detect an interaction between quinine and OCTN1, which is most likely a result of the lower concentrations used in our experiments.

In summary, we characterized OATP2B1 and OATP1A2 expression in RBCs and were able to demonstrate OATP1A2-dependent transport of the antimalarial drug quinine. Therefore, intracellular drug concentration within RBCs is determined not only by passive uptake and active efflux processes but also by uptake transporters such as OATP1A2. As a consequence, environmental, pharmacologic, and/or genetic modification of OATP1A2 function may affect intracellular concentration and activity of quinine in antimalarial therapy.

Acknowledgments

The authors thank Tina Sonnenberger (Department of Pharmacology, University Medicine, Greifswald, Germany) for the excellent technical assistance.

Authorship Contributions

Participated in research design: Hubeny, Grube.

Conducted experiments: Hubeny, Grube.

Contributed new reagents or analytic tools: Hubeny, Keiser, Oswald.

Performed data analysis: Hubeny, Grube.

Wrote or contributed to the writing of the manuscript: Hubeny, Grube, Jedlitschky, Siegmund, Kroemer.

Footnotes

    • Received February 2, 2016.
    • Accepted August 4, 2016.
  • ↵1 Current affiliation: University Medicine Göttingen, Göttingen, Germany.

  • This work was supported by the German Federal Ministry for Education and Research [grant 03IPT612X].

  • dx.doi.org/10.1124/dmd.116.069807.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

Abbreviations

ABC
ATP-binding cassette
E1S
estrone-3-sulfate
MDCKII
Madin-Darby canine kidney cells
MPP+
1-methyl-4-phenylpyridinium
OATP
organic anion transporting polypeptide
OCT
organic cation transporter
OCTN
organic cation transporter novel type
PBS
phosphate-buffered saline
P-gp
P-glycoprotein
RBC
red blood cell
SLC
solute carrier
TEA
tetraethylammonium
  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics

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Drug Metabolism and Disposition: 44 (10)
Drug Metabolism and Disposition
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Research ArticleArticle

OATP1A2 and Antimalarial Compounds

Andrea Hubeny, Markus Keiser, Stefan Oswald, Gabriele Jedlitschky, Heyo K. Kroemer, Werner Siegmund and Markus Grube
Drug Metabolism and Disposition October 1, 2016, 44 (10) 1562-1568; DOI: https://doi.org/10.1124/dmd.116.069807

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Research ArticleArticle

OATP1A2 and Antimalarial Compounds

Andrea Hubeny, Markus Keiser, Stefan Oswald, Gabriele Jedlitschky, Heyo K. Kroemer, Werner Siegmund and Markus Grube
Drug Metabolism and Disposition October 1, 2016, 44 (10) 1562-1568; DOI: https://doi.org/10.1124/dmd.116.069807
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