Interaction Of Chloroquine Research Articles

Potential Effect of Chloroquine in Modulating Hyperglycemia and PTEN Receptor Linked Dyslipidemia on Alloxan-induced Diabetic Mice

Background: Diabetes mellitus is a life-threatening disease associated with worsening of glycemic control, progressive metabolic dysfunctions and disruption of the Phosphatase and Tensin Homolog (PTEN) receptor. Purpose: To evaluate the effect of chloroquine on blood glucose level and lipid profile of alloxan-induced diabetic mice and to observe its interaction with PTEN, a negative regulator of insulin signaling pathway. Methodology: Thirty mice were used for the experiment. A group (n = 5) was kept as healthy control while the others were pre-treated with 140 mg/kg of alloxan monohydrate in distilled water. The alloxan-induced diabetic mice were randomly divided into four groups: diabetic model control group, 60 mg/kg chloroquine, 120 mg/kg chloroquine, and 10 mg/kg glibenclamide treatment groups respectively. Treatment was done once daily for seven days and the blood glucose level was investigated acutely and then daily throughout the experimental period. A molecular docking study was also conducted to evaluate the interaction of chloroquine with PTEN using PYRX software, while an automated COBAS C 311 machine was used to analyze the lipid profile after the treatment period. Results: Oral administration of chloroquine gradually and significantly lowered the raised blood glucose level in a time- and dose-dependent manner. A repeated study with 120 mg/kg of chloroquine revealed a decline in blood sugar from 221.5 ± 3.6 on day 1 to 85.5 ± 2.4 on day 7 in comparison to glibenclamide, whose sugar level was reduced to 75.5 ± 3.7 at the end of day 7. The docking study revealed a non-competitive inhibition with an inhibition score of -6.1 in comparison to metformin, which had a score of -4.4, and glibenclamide, which had a score of -9.0. This interaction resulted in a conformational change of the receptor, hence, enhancing glucose uptake and reducing the raised hyperglycemia. Treatment with chloroquine was also observed to reduce the total cholesterol and triglyceride levels from 162 in the model group to 144 and 141 to 116 mmol/L, respectively. The levels of low-density lipoprotein cholesterol (LDL-C) and very low-density lipoprotein (VLDL) following treatment with chloroquine were not statistically different from the non-diabetic healthy mice. These values were very similar to those obtained with glibenclamide-treated diabetic mice. Conclusion: From the results, chloroquine possesses potent antidiabetic properties and can improve dyslipidemia imposed by hyperglycemia probably owing to its inhibition of PTEN, a negative regulator of insulin resistance.

Pharmacodynamic Modeling Identifies Synergistic Interaction Between Chloroquine and Trastuzumab in Refractory HER2- positive Breast Cancer Cells.

Despite improvements in HER2-positive breast cancer (BC) patients' outcomes with trastuzumab, the occurrence of intrinsic or acquired resistance presents a clinical challenge. Here, we quantitatively assess the combinatorial effects of chloroquine, an autophagy inhibitor, with trastuzumab on JIMT-1 cells, a HER2-positive BC cell-line primarily resistant to trastuzumab. The temporal changes in JIMT-1 cellular viability were assessed using the CCK-8 kit, where JIMT-1 cells were exposed for 72-h to trastuzumab (0.007-17.19 μM) or chloroquine (5-50 μM) as single-agents, in combination (trastuzumab: 0.007-0.688 μM; chloroquine: 5-15 μM), or control (no drug). Concentration-response relationships were built for each treatment arm to determine drugs' concentrations inducing 50% of cell-killing (IC50). Cellular pharmacodynamic models were built to characterize the time-trajectory of JIMT-1 cellular viability under each treatment arm. The nature of trastuzumab and chloroquine interaction was quantified by estimating the interaction parameter (Ψ). The IC50 were estimated at 19.7 and 24.4 μM for trastuzumab and chloroquine. The maximum killing effect was about thrice higher for chloroquine than trastuzumab (0.0405 vs. 0.0125 h-1), validating chloroquine's superior anti-cancer effect on JIMT-1 cells compared to trastuzumab. The time-delay for chloroquine cell-killing was twice longer than that for trastuzumab (17.7 vs. 7 h), suggesting a chloroquine time-dependent anti-cancer effect. The Ψ was determined at 0.529 (Ψ<1), indicating a synergistic interaction. This proof-of-concept study on JIMT-1 cells identified chloroquine and trastuzumab synergistic interaction, warranting further in vivo investigations.

Boron nitride nanocage as drug delivery systems for chloroquine, as an effective drug for treatment of coronavirus disease: A DFT study

Research has shown that chloroquine (CQ) can effectively help control COVID-19 infection. B24N24 nanocage is a drug delivery system. Thus, through density functional theory, the present study analyzed pristine nanocage-CQ interaction and CQ interaction with Si- and Al -doped nanocage. The findings revealed that nanocage doping, particularly with Si and Al, yields more satisfactory drug delivery for CQ due to their greater electronic and energetic characteristics with CQ.

Interaction of chloroquine with 2-(hydroxypropyl)-β-cyclodextrin through the supramolecular assembly for cytotoxicity on breast cancer cell lines

Interaction of chloroquine with 2-(hydroxypropyl)-β-cyclodextrin through the supramolecular assembly for cytotoxicity on breast cancer cell lines

Metabolism and Interactions of Chloroquine and Hydroxychloroquine with Human Cytochrome P450 Enzymes and Drug Transporters.

In clinical practice, chloroquine and hydroxychloroquine are often co-administered with other drugs in the treatment of malaria, chronic inflammatory diseases, and COVID-19. Therefore, their metabolic properties and the effects on the activity of cytochrome P450 (P450, CYP) enzymes and drug transporters should be considered when developing the most efficient treatments for patients. Scientific literature on the interactions of chloroquine and hydroxychloroquine with human P450 enzymes and drug transporters, was searched using PUBMED.Gov (https://pubmed.ncbi.nlm.nih.gov/) and the ADME database (https://life-science.kyushu.fujitsu.com/admedb/). Chloroquine and hydroxychloroquine are metabolized by P450 1A2, 2C8, 2C19, 2D6, and 3A4/5 in vitro and by P450s 2C8 and 3A4/5 in vivo by N-deethylation. Chloroquine effectively inhibited P450 2D6 in vitro; however, in vivo inhibition was not apparent except in individuals with limited P450 2D6 activity. Chloroquine is both an inhibitor and inducer of the transporter MRP1 and is also a substrate of the Mate and MRP1 transport systems. Hydroxychloroquine also inhibited P450 2D6 and the transporter OATP1A2. Chloroquine caused a statistically significant decrease in P450 2D6 activity in vitro and in vivo, also inhibiting its own metabolism by the enzyme. The inhibition indicates a potential for clinical drug-drug interactions when taken with other drugs that are predominant substrates of the P450 2D6. When chloroquine and hydroxychloroquine are used clinically with other drugs, substrates of P450 2D6 enzyme, attention should be given to substrate-specific metabolism by P450 2D6 alleles present in individuals taking the drugs.

Molecular Docking Study of the Interactions between Plasmodium falciparum Lactate Dehydrogenase and 4-Aminoquinoline Hybrids

Malaria is a potentially deadly disease with many anti-malarial drugs have been rendered ineffective due to Plasmodium falciparum resistance concern. Plasmodium falciparum lactate dehydrogenase (PfLDH) enzyme is a crucial malaria parasite enzyme involved in the glycolytic pathway, thus, has been considered as a potential molecular target. Initially, molecular docking was performed using AutoDock Vina, Molegro Virtual Docker, and CDOCKER software to investigate the molecular interactions of 4-aminoquinoline antimalarial hybrids compounds with PfLDH enzyme. All ten 4-aminoquinoline hybrids derivatives docked to the PfLDH binding site. The results showed that these compounds exhibited either comparable or higher binding affinity than the reference drug chloroquine, amodiaquine, and hydroxychloroquine. Visually, some of the compounds possessed functional binding interactions, possibly due to their similar structural conformation and binding interactions of chloroquine in the binding site. Apart from that, the docking results also suggest that these compounds potentially promote additional hydrogen-bonding interactions with the residues in the binding site. Interestingly, the compounds also predicted to interact with essential PHE52, VAL26, ILE54, ILE119, and ALA98 residues, which are required to act as a competitive inhibitor for this glycolytic enzyme.

Docking study of chloroquine and hydroxychloroquine interaction with RNA binding domain of nucleocapsid phospho-protein – an in silico insight into the comparative efficacy of repurposing antiviral drugs

Recent outbreak of novel Coronavirus disease () pandemic around the world is associated with severe acute respiratory syndrome. The death toll associated with the pandemic is increasing day by day. SARS-CoV-2 is an enveloped virus and its N terminal domain (NTD) of Nucleocapsid protein (N protein) binds to the viral (+) sense RNA and results in virus ribonucleoprotien complex, essential for the virus replication. The N protein is composed of a serine-rich linker region sandwiched between NTD and C terminal (CTD). These terminals play a role in viral entry and its processing post entry. The NTD of SARS-CoV-2 N protein forms orthorhombic crystals and binds to the viral genome. Therefore, there is always a quest to target RNA binding domain of nucleocapsid phosphoprotein (NTD-N-protein which in turn may help in controlling diseases caused by SARS-CoV-2 in humans. The role of Chloroquine and Hydroxychloroquine as potential treatments for is still under debate globally because of some side effects associated with it. This study involves the In silico interactions of Chloroquine and Hydroxychloroquine with the NTD-N-protein of SARS-CoV-2. With the help of various computational methods, we have explored the potential role of both of these antiviral drugs for the treatment of patients by comparing the efficacy of both of the drugs to bind to NTD-N-protein. In our research Hydroxychloroquine exhibited potential inhibitory effects of NTD-N-protein with binding energy −7.28 kcal/mol than Chloroquine (−6.30 kcal/mol) at SARS-CoV-2 receptor recognition of susceptible cells. The outcomes of this research strongly appeal for in vivo trials of Hydroxychloroquine for the patients infected with . Furthermore, the recommended doses of Hydroxychloroquine may reduce the chances of catching to the healthcare workers and staff who are in contact with or delivering direct care to coronavirus patients as long as they have not been diagnosed with . We further hypothesize that the comparative NTD-N-protein -drug docking interactions may help to understand the comparative efficacy of other candidate repurposing drugs until discovery of a proper vaccine. Communicated by Ramaswamy H. Sarma

In-silico strategies for probing chloroquine based inhibitors against SARS-CoV-2

The global health emergency of novel COVID-19 is due to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Currently there are no approved drugs for the treatment of coronaviral disease (COVID-19), although some of the drugs have been tried. Chloroquine is being widely used in treatment of SARS-CoV-2 infection. Hydroxychloroquine, the derivative of Chloroquine shows better inhibition than Chloroquine and has in vitro activity against SARS-CoV-2 also used to treat COVID-19. To study the interactions of Chloroquine and derivatives of Chloroquine with SARS-CoV-2, series of computational approaches like pharmacophore model, molecular docking, MM_GBSA study and ADME property analysis are explored. The pharmacophore model and molecular docking study are used to explore the structural properties of the compounds and the ligand-receptor (PDB_ID: 6LU7) interactions respectively. MM_GBSA study gives the binding free energy of the protein-ligand complex and ADME property analysis explains the pharmacological property of the compounds. The resultant best molecule (CQD15) further subjected to molecular dynamics (MD) simulation study which explains the protein stability (RMSD), ligand properties as well as protein-ligand contacts. Outcomes of the present study conclude with the molecule CQD15 which shows better interactions for the inhibition of SARS-CoV-2 in comparison to Chloroquine and Hydroxychloroquine. Communicated by Ramaswamy H. Sarma

Investigating the role of endogenous opioid system in chloroquine-induced phospholipidosis in rat liver by morphological, biochemical and molecular modelling studies.

Drug-induced phospholipidosis (DIPL) is characterized by phospholipid storage in the lysosomes of affected tissues. Many severe effects and toxicities have been linked to DIPL. The aim of this study was to determine whether the endogenous opioid system is involved in chloroquine-induced phospholipidosis. The effect of naltrexone as an antagonist of opioid receptors in chloroquine-induced phospholipidosis in rat liver was investigated by morphological, biochemical, and molecular modelling studies. Transmission electron microscopy (TEM) showed that morphological characteristic changes of rat liver, including the number of lamellar bodies, grade of vacuolization and cell steatosis, were markedly attenuated in rats treated with naltrexone alone or in combination with chloroquine, in comparison with chloroquine-treated rats. The results of liquid chromatography mass spectrometry (LC/MS) showed that the concentrations of phenylacetylglycine (PAG) and hippuric acid (HA) were significantly decreased and increased, respectively, in target groups. Besides, the concentration ratio of PAG/HA was significantly decreased. Spectrophotometry resulted in a notable decrease in alanine aminotransferase (ALT) and alkaline phosphatase (ALP) activities in target groups. The results from the molecular docking and molecular dynamic simulation studies demonstrated clear chloroquine interaction with the active site cavity of the µopioid receptor. These data suggest that administration of naltrexone alone, or in combination with chloroquine, notably attenuates the side effects of chloroquine-induced phospholipidosis, as well as demonstrating an increased probability of the endogenous opioid system involvement in chloroquine-induced phospholipidosis in rat liver.

Metabolism and Interactions of Chloroquine and Hydroxychloroquine with Human Cytochrome P450 Enzymes and Drug Transporters

Metabolism and Interactions of Chloroquine and Hydroxychloroquine with Human Cytochrome P450 Enzymes and Drug Transporters

Interactive effects of alcohol and chloroquine on hematologic profile of Wistar rats.

Abstract Background There is paucity of information on the adverse effects of alcohol – chloroquine interaction on hematological parameters. To investigate the effects of concurrent administration of chloroquine and ethanol on hematologic parameters of adult Wistar rats and the ameliorative role of vitamin B12 and folic acid supplementation on any adverse effects. Methods Some 30 adult Wistar rats weighing 120–200 g were assigned to six major groups of five rats each according to their weights. The control group A was fed with normal rat chow and water. The experimental groups B–F were administered with drugs for a period of 7 days as follows: B (chloroquine only); C (ethanol only); D (chloroquine+ethanol); E (chloroquine+ethanol+vitamin B12); and F (chloroquine+ethanol+vitamin B12+folic acid). Blood samples were collected from each animal by cardiac puncture to determine red blood cell (RBC) count, white blood cell (WBC) count, packed cell volume (PCV), hemoglobin (Hb), mean corpuscular hemoglobin concentration, mean cell volume (MCV), and mean cell hemoglobin (MCH). Liver enzymes, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) were analyzed to test for liver function. Results Group D indicated lower PCV, Hb, MCV, MCH, and greater WBC compared with control. Group E indicated greater (p&lt;0.05) PCV, Hb, and RBC compared with Group D. Greater (p&lt;0.05) MCV and MCH, and lower WBC and RBC were observed in Group F compared with Group D. Furthermore, Group D rats indicated greater (p&lt;0.05) mean AST and ALT compared with Groups A, E, and F. Conclusions Concurrent administration of chloroquine and alcohol indicated adverse effects on hematologic parameters of Wistar rats. The administration of vitamin B12 and folic acid appeared to ameliorate these adverse effects.

Interaction of Iron(III)-5,10,15,20-Tetrakis (4-Sulfonatophenyl) Porphyrin with Chloroquine, Quinine and Quinidine

Iron(III)-5,10,15,20-tetrakis(4-sulfonatophenyl) porphyrin (FeTPPS) is used as non-physiological metalloporphyrin model for the natural iron (III)-protoporphyrin IX (FePPIX) resulting from hemoglobin degradation to investigate ligand binding reactions in aqueous solution. Studies were conducted on the interaction of FeTPPS with Chloroquine, Quinine, and Quinidine, which are historically the most common quinoline-based drugs used to treat malaria, an infectious disease afflicting several hundred millions every year worldwide, mainly in tropical regions. Using UV-Visible spectrophotometry, the binding reaction was studied at pH 7.40 in purely aqueous solution, and in aqueous solution containing NaNO3 at concentration of 0.1 M. Fitted titration curves obtained were in agreement with experimental data according to a formation scheme of 1:1 complex (1 FeTPPS μ-oxo-dimer: 1 Antimalarial). Values of apparent binding constant (K) obtained were between 4.3 × 103 M-1 to 7.59 × 104 M-1, demonstrating that FeTPPS and the antimalarials formed stable complexes. The stability of the complex decreased when NaNO3 was added to the solution. This ionic strength dependence was ascribed to electrostatic effects. Quinine and Chloroquine interacted with FeTPPS stronger than Quinidine did. Chloroquine showed the strongest affinity to FeTPPS. These findings revealed the influence of steric and stereochemical factors. Molecular electrostatic potentials (MEP) calculated with Hartree-Fock theory argue in favor of π-π and electrostatic interactions between reaction partners as driving forces for the complex formation. In the case of FeTPPS: Chloroquine interaction, it is suggested that an intramolecular hydrogen bond is formed between phenyl and quinuclidine N-H+ as additional force stabilizing the complex. Analysis of crystallographic data using the Cambridge Structural Database (CSD) gave evidence of the hydrogen bond formation between phenyl and N-H+ groups in 370 structures.

Solution structures of chloroquine–ferriheme complexes modeled using MD simulation and investigated by EXAFS spectroscopy

The interaction of chloroquine (CQ) and the μ-oxo dimer of iron(III) protoporphyrin IX (ferriheme) in aqueous solution was modeled using molecular dynamics (MD) simulations. Two models of the CQ-(μ-oxo ferriheme) complex were investigated, one involving CQ π-stacked with an unligated porphyrin face of μ-oxo ferriheme and the other in which CQ was docked between the two porphyrin rings. The feasibility of both models was tested by fitting computed structures to the experimental extended X-ray absorption fine structure (EXAFS) spectrum of the CQ-(μ-oxo ferriheme) complex in frozen aqueous solution. The docked model produced better agreement with experimental data, suggesting that this is the more likely structure in aqueous solution. The EXAFS fit indicated a longer than expected Fe–O bond of 1.87Å, accounting for the higher than expected magnetic moment of the complex. As a consequence, the asymmetric Fe–O–Fe stretch shifts much lower in frequency and was identified in the precipitated solid at 744cm−1 with the aid of the O18 isomer shift. Three important CQ-ferriheme interactions were identified in the docked structure. These were a hydrogen bond between the oxide bridge of μ-oxo ferriheme and the protonated quinolinium nitrogen atom of CQ; π-stacking between the quinoline ring of CQ and the porphyrin rings; and a close contact between the 7-chloro substituent of CQ and the porphyrin methyl hydrogen atoms. These interactions can be used to rationalize previously observed structure–activity relationships for quinoline–ferriheme association.

Synergistic activity of chloroquine with fluconazole against fluconazole-resistant isolates of Candida species.

The in vitro activity of chloroquine and the interactions of chloroquine combined with fluconazole against 37 Candida isolates were tested using the broth microdilution, disk diffusion, and Etest susceptibility tests. Synergistic effect was detected with 6 of 9 fluconazole-resistant Candida albicans isolates, with Candida krusei ATCC 6258, and with all 12 fluconazole-resistant Candida tropicalis isolates.

Atovaquone and quinine anti-malarials inhibit ATP binding cassette transporter activity.

BackgroundTherapeutic blood plasma concentrations of anti-malarial drugs are essential for successful treatment. Pharmacokinetics of pharmaceutical compounds are dependent of adsorption, distribution, metabolism, and excretion. ATP binding cassette (ABC) transport proteins are particularly involved in drug deposition, as they are located at membranes of many uptake and excretory organs and at protective barriers, where they export endogenous and xenobiotic compounds, including pharmaceuticals. In this study, a panel of well-established anti-malarial drugs which may affect drug plasma concentrations was tested for interactions with human ABC transport proteins.MethodsThe interaction of chloroquine, quinine, artemisinin, mefloquine, lumefantrine, atovaquone, dihydroartemisinin and proguanil, with transport activity of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), bile salt export pump (BSEP) and multidrug resistance-associated proteins (MRP) 1–4 were analysed. The effect of the anti-malarials on the ATP-dependent uptake of radio-labelled substrates was measured in membrane vesicles isolated from HEK293 cells overexpressing the ABC transport proteins.ResultsA strong and previously undescribed inhibition of BCRP-mediated transport by atovaquone with a 50% inhibitory concentration (IC50) of 0.23 μM (95% CI 0.17-0.29 μM) and inhibition of P-gp-mediated transport by quinine with an IC50 of 6.8 μM (95% CI 5.9-7.8 μM) was observed. Furthermore, chloroquine and mefloquine were found to significantly inhibit P-gp-mediated transport. BCRP transport activity was significantly inhibited by all anti-malarials tested, whereas BSEP-mediated transport was not inhibited by any of the compounds. Both MRP1- and MRP3-mediated transport were significantly inhibited by mefloquine.ConclusionsAtovaquone and quinine significantly inhibit BCRP- and P-gp- mediated transport at concentrations within the clinically relevant prophylactic and therapeutic range. Co-administration of these established anti-malarials with drugs that are BCRP or P-gp substrates may potentially lead to drug-drug interactions.

EPA-1255 – Behavioral symptoms in patients with systemic lupus erythematosus induced by chloroquine-a report of two cases

It is difficult to differentiate whether neuropsychiatric symptoms are caused by systemic lupus erythematosus (SLE) or psychiatric background, coexisting disorders or drug-induced side effects. The aim of this paper is to present two cases of psychotic symptoms (bipolar and paranoid disorder) induced by chloroquine. Case 1: Severe depressive episode with psychotic features appeared in the context of third SLE exacerbation and chloroquine treatment. Hydroxychloroquine was used instead and symptoms resolved. Later, manic episode (with psychotic features) emerged several days after chloroquine was prescribed for concomitant arthritis. Since that time, chloroquine has been withdrawn. Currently the patient is undergoing treatment with hydroxychloroquine and psychiatric drugs with good response. Case 2: The second patient started to suffer from headaches and being lightheaded three days after chloroquine administration and within next few days feeling of derealization and poorly defining persecutory delusions accompanied by strong anxiety with occasional visual illusions occurred with clear consciousness. After eighteen days chloroquine was withdrawn and after two days all the symptoms resolved. Clinicians should be vigilant for possible psychiatric disorder when using chloroquine in patients with SLE. Such cases are probably rare and may include both paranoid and bipolar spectrum disorders. Studies on interactions of chloroquine with brain neurotransmitter systems are needed. Hydroxychloroquine may represent lower risk considering psychiatric complications. Mechanism of the difference is currently not known.

Molecular Mechanisms of Chloroquine Inhibition of Heterologously Expressed Kir6.2/SUR2A Channels

Chloroquine and related compounds can inhibit inwardly rectifying potassium channels by multiple potential mechanisms, including pore block and allosteric effects on channel gating. Motivated by reports that chloroquine inhibition of cardiac ATP-sensitive inward rectifier K(+) current (I(KATP)) is antifibrillatory in rabbit ventricle, we investigated the mechanism of chloroquine inhibition of ATP-sensitive potassium (K(ATP)) channels (Kir6.2/SUR2A) expressed in human embryonic kidney 293 cells, using inside-out patch-clamp recordings. We found that chloroquine inhibits the Kir6.2/SUR2A channel by interacting with at least two different sites and by two mechanisms of action. A fast-onset effect is observed at depolarized membrane voltages and enhanced by the N160D mutation in the central cavity, probably reflecting direct channel block resulting from the drug entering the channel pore from the cytoplasmic side. Conversely, a slow-onset, voltage-independent inhibition of I(KATP) is regulated by chloroquine interaction with a different site and probably involves disruption of interactions between Kir6.2/SUR2A and phosphatidylinositol 4,5-bisphosphate. Our findings reveal multiple mechanisms of K(ATP) channel inhibition by chloroquine, highlighting the numerous convergent regulatory mechanisms of these ligand-dependent ion channels.

Analysis of the molecular interactions and complexation of chloroquine with bovine serum albumin

Pharmacokinetic parameters, drug bioavailability, and biological activities depend on the mechanisms of interaction with serum albumin. In this study, the binding properties as well as mechanisms of interaction of chloroquine with bovine serum albumin (BSA) were investigated. The binding of chloroquine with BSA was carried out using a microcalorimetric approach. The mechanism of binding, the number of binding molecules as well as changes of BSA upon complexation with chloroquine were investigated. The binding isotherms indicated a variable number of binding sites of chloroquine on one molecule of BSA. At lower temperatures, larger numbers of binding sites were available for chloroquine, these decrease by increasing the temperature. The binding constant of chloroquine with BSA varied from 9.4×10³ M⁻¹ at 25°C to 5.7×10³ M⁻¹ at 40°C. Chloroquine showed temperature-dependent binding affinity, with stronger affinity at lower temperature. By increasing the temperature, from 25°C to 40°C, the binding affinity was decreased by approximately 60% of its value. Chloroquine showed weak binding affinity with BSA. The weak binding affinity of chloroquine with BSA is important in determining the drug-drug interactions at the binding sites of BSA. The presence of stronger binding ligands, e.g., chloramphenicol, tetracyclines or diclofenac, can compete with chloroquine for its binding sites, and therefore lowers its serum albumin binding. This study will be helpful in understanding the binding properties of mechanisms of interaction of chloroquine with BSA.

Molecular Mechanism of Renal Tubular Secretion of the Antimalarial Drug Chloroquine

The antimalarial drug chloroquine is eliminated to a significant extent by renal tubular secretion. The molecular mechanism of renal chloroquine secretion remains unknown. We hypothesized that organic cation transporter 2 (OCT2) and multidrug and toxin extrusion protein 1 (MATE1), localized in the basolateral and luminal membranes of proximal tubule cells, respectively, are involved in chloroquine transport. The interaction of chloroquine with both transporters was investigated using single-transfected human embryonic kidney 293 (HEK293)-MATE1 cells in uptake experiments and single-transfected Madin-Darby canine kidney II (MDCK)-OCT2 and MDCK-MATE1 cells as well as double-transfected MDCK-OCT2-MATE1 cells grown as polarized monolayers on transwell filters. In HEK293-MATE1 cells, chloroquine competitively inhibited MATE1-mediated metformin uptake (K(i) = 2.8 μM). Cellular accumulation of chloroquine was significantly lower (P < 0.001) and transcellular chloroquine transport was significantly increased (P < 0.001) in MDCK-MATE1 and MDCK-OCT2-MATE1 cells compared to vector control cells after basal addition of chloroquine (0.1 to 10 μM). In contrast, no difference in cellular accumulation or transcellular transport of chloroquine was observed between MDCK-OCT2 and vector control cells. In line with an oppositely directed proton gradient acting as a driving force for MATE1, basal-to-apical transport of chloroquine by MDCK-OCT2-MATE1 cells increased with decreasing apical pH from 7.8 to 6.0. Transcellular transport of chloroquine by MDCK-OCT2-MATE1 cells was inhibited by cimetidine, trimethoprim, and amitriptyline. Our data demonstrate that chloroquine is a substrate and potent competitive inhibitor of MATE1, whereas OCT2 seems to play no role in chloroquine uptake. Concomitantly administered MATE1 inhibitors are likely to modify the renal secretion of chloroquine.

A calorimetric study of chloroquine interaction with phosphatidyl choline vesicles [proceedings

A calorimetric study of chloroquine interaction with phosphatidyl choline vesicles [proceedings