Intracellular ABCB1 as a Possible Mechanism to Explain the Synergistic Effect of Hydroxychloroquine-Azithromycin Combination in COVID-19 Therapy
Jm. M Scherrmann
The AAPS Journal, doi:10.1208/s12248-020-00465-w
The co-administration of hydroxychloroquine with azithromycin is proposed in COVID-19 therapy. We hypothesize a new mechanism supporting the synergistic interaction between these drugs. Azithromycin is a substrate of ABCB1 (P-glycoprotein) which is localized in endosomes and lysosomes with a polarized substrate transport from the cell cytosol into the vesicle interior. SARS-CoV-2 and drugs meet in these acidic organelles and both basic drugs, which are potent lysosomotropic compounds, will become protonated and trapped within these vesicles. Consequently, their intra-vesicular concentrations can attain low micromolar effective cytotoxic concentrations on SARS-CoV-2 while concomitantly increase the intra-vesicular pH up to around neutrality. This last effect inhibits lysosomal enzyme activities responsible in virus entry and replication cycle. Based on these considerations, we hypothesize that ABCB1 could be a possible enhancer by confining azithromycin more extensively than expected when the trapping is solely dependent on the passive diffusion. This additional mechanism may therefore explain the synergistic effect when azithromycin is added to hydroxychloroquine, leading to apparently more rapid virus clearance and better clinical benefit, when compared to monotherapy with hydroxychloroquine alone.
References
Al-Rawi, Meggitt, Williams, Wahie, Steady-state pharmacokinetics of hydroxychloroquine in patients with cutaneous lupus erythematosus, Lupus
Amsden, Nafziger, Foulds, Cabelus, A study of the pharmacokinetics of azithromycin and nelfinavir when coadministered in healthy volunteers, J Clin Pharmacol
Bonam, Wang, Muller, Lysosomes as a therapeutic target, Nat Rev Drug Discov
Borst, Schinkel, P-glycoprotein ABCB1: a major player in drug handling by mammals, J Clin Invest
Chen, Liu, Liu, Xia, Ling, A pilot study of hydroxychloroquine in treatment of patients with common coronavirus disease-19 (COVID-19), J Zhejiang Univ (Med Sci)
Chico, Chandramohan, Azithromycin plus chloroquine: combination therapy for protection against malaria and sexually transmitted infections in pregnancy, Expert Opin Drug Metab Toxicol
Damle, Vourvahis, Wang, Leaney, Corrigan, Clinical pharmacology perspectives on the antiviral activity of azithromycin and use in COVID-19, Clin Pharmacol Ther,
doi:10.1002/cpt.1857
Davidson, In vitro activity and pharmacodynamic/ pharmacokinetic parameters of clarithromycin and azithromycin: why they matter in the treatment of respiratory tract infections, Infect Drug Resist
Devaux, Rolain, Colson, Raoult, New insights on the antiviral effects of chloroquine against coronavirus: what to expect for COVID-19?, Int J Antimicrob Agents,
doi:10.1016/j.ijantimicag.2020.105938
Dey, Bishayi, Killing of Staphylococcus aureus in murine macrophages by chloroquine used alone and in combination with ciprofloxacin or azithromycin, J Inflamm Res
Dumitrescu, Anic-Milic, Oreskovic, Padovan, Brouwer et al., Development of a population pharmacokinetic model to describe azithromycin whole-blood and plasma concentrations over time in healthy subjects, Antimicrob Agents Chemother
El-Tahtawy, Glue, Andrews, Mardekian, Amsden et al., The effect of azithromycin on ivermectin pharmacokinetics-a population pharmacokinetic model analysis, PLoS Negl Trop Dis
Fu, Arias, Intracellular trafficking of P-glycoprotein, Int J Biochem Cell Biol
Funk, Krise, Cationic amphiphilic drugs cause a marked expansion of apparent lysosomal volume: implications for an intracellular distribution-based drug interaction, Mol Pharm
G B I N I G I E K , F R I E K . S H O U L D C, h l o r o q u i n e a n d hydroxychloroquine be used to treat COVID-19? A rapid review,
doi:10.3399/bjgpopen20X101069
Gameiro, Silva, Rocha-Pereira, Carmo, Carvalho et al., Cellular models and In vitro assays for the screening of modulators of P-gp, MRP1 and BCRP, Molecules,
doi:10.3390/molecules22040600
Gao, Tian, Yang, Breakthrough: chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies, Biosci Trends
Garcia-Cremades, Solans, Hughes, Ernest, Wallender et al., Optimizing hydroxychloroquine dosing for patients with COVID-19: an integrative modeling approach for effective drug repurposing, Clin Pharmacol Ther,
doi:10.1002/cpt.1856
Gautret, Lagier, Parola, Hoang, Meddeb et al., Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial, Int J Antimicrob Agents,
doi:10.1016/j.ijantimicag.2020.105949
Gingras, Jensen, Activity of azithromycin (CP-62,993) and erythromycin against chloroquine-sensitive and chloroquine-resistant strains of plasmodium falciparum in vitro, Am J Trop Med Hyg
Hayeshi, Masimirembwa, Mukanganyama, Ungell, The potential inhibitory effect of antiparasitic drugs and natural products on P-glycoprotein mediated efflux, Eur J Pharm Sci
He, Zhao, Qiu, Sun, Li-Ling, Influence of ABCB1 gene polymorphisms on the pharmacokinetics of azithromycin among healthy Chinese Han ethnic subjects, Pharmacol Rep
Jin, Luong, Reese, Gaona, Collazo-Velez et al., Comparison of MDCK-MDR1 and Caco-2 cell based permeability assays for anti-malarial drug ing and drug investigations, J Pharmacol Toxicol Methods
Kannan, Brimacombe, Kreisl, Liow, Zoghbi et al., Lysosomal trapping of a radiolabeled substrate of P-glycoprotein as a mechanism for signal amplification in PET, Proc Natl Acad Sci U S A
Katayama, Kapoor, Ohnuma, Patel, Swaim et al., Revealing the fate of cell surface human P-glycoprotein (ABCB1): the lysosomal degradation pathway, Biochim Biophys Acta
Kazmi, Hensley, Pope, Funk, Loewen et al., Lysosomal sequestration (trapping) of lipophilic amine (cationic amphiphilic) drugs in immortalized human hepatocytes (Fa2N-4 cells), Drug Metab Dispos
Keshtkar-Jahromi, Bavari, A call for randomized controlled trials to test the efficacy of chloroquine and hydroxychloroquine as therapeutics against novel coronavirus disease (COVID-19), Am J Trop Med Hyg
Kim, Drugs as P-glycoprotein substrates, inhibitors, and inducers, Drug Metab Rev
Kshirsagar, Gogtay, Moran, Utz, Sethia et al., Treatment of adults with acute uncomplicated malaria with azithromycin and chloroquine in India, Colombia, and Suriname, Res Rep Trop Med
Leden, Digoxin-hydroxychloroquine interaction?, Acta medica Scandinavica
Liu, Cao, Xu, Wang, Zhang et al., Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro, Cell Discov
Liu, Li, Zhang, Kwong, Li et al., Chloroquine and hydroxychloroquine are associated with reduced cardiovascular risk: a systematic review and meta-analysis, Drug Des Dev Ther
Liu-Kreyche, Shen, Marino, Iyer, Humphreys et al., Lysosomal P-gp-MDR1 confers drug resistance of brentuximab vedotin and its cytotoxic payload monomethyl auristatin E in tumor cells, Front Pharmacol
Maa, Targeting endosomal acidification by chloroquine analogs as a promising strategy for the treatment of emerging viral diseases, Pharmacol Res Perspect
Madrid, Panchal, Warren, Shurtleff, Endsley et al., Evaluation of Ebola virus inhibitors for drug repurposing, ACS Infect Dis
Munic, Kelneric, Mikac, Erakovic, Differences in assessment of macrolide interaction with human MDR1 (ABCB1, P-gp) using rhodamine-123 efflux, ATPase activity and cellular accumulation assays, Eur J Pharm Sci
Nazir, Gul, Ali, Saleha, Khan, The effect of gender and ABCB1 gene polymorphism on the pharmacokinetics of azithromycin in healthy male and female Pakistani subjects, Can J Physiol Pharmacol,
doi:10.1139/cjpp-2019-0569
Nujic, Banjanac, Munic, Polancec, Erakovic, Impairment of lysosomal functions by azithromycin and chloroquine contributes to anti-inflammatory phenotype, Cell Immunol
Ohe, Shida, Jodo, Kusunoki, Seki et al., Macrolide treatment for COVID-19: will this be the way forward?, Biosci Trends,
doi:10.5582/bst.2020.03058
Pereira, Henrich, Sidhu, Johnson, Hardink et al., In vivo and in vitro antimalarial properties of azithromycin-chloroquine combinations that include the resistance reversal agent amlodipine, Antimicrob Agents Chemother
Poschet, Perkett, Timmins, Deretic, Azithromycin and ciprofloxacin have a chloroquine-like effect on respiratory epithelial cells, bioRxiv,
doi:10.1101/2020.03.29.008631
Rajagopal, Simon, Subcellular localization and activity of multidrug resistance proteins, Mol Biol Cell
Rijpma, Van Den Heuvel, Van Der Velden, Sauerwein, Russel et al., Atovaquone and quinine antimalarials inhibit ATP binding cassette transporter activity, Malar J
Savarino, Boelaert, Cassone, Majori, Cauda, Effects of chloroquine on viral infections: an old drug against today's diseases?, Lancet Infect Dis
Savarino, Use of chloroquine in viral diseases, Lancet Infect Dis
Seral, Van Bambeke, Tulkens, Quantitative analysis of gentamicin, azithromycin, telithromycin, ciprofloxacin, moxifloxacin, and oritavancin (LY333328) activities against intracellular Staphylococcus aureus in mouse J774 macrophages, Antimicrob Agents Chemother
Sironi, Aranda, Nordstrom, Schwartz, Lysosome membrane permeabilization and disruption of the molecular target of rapamycin (mTOR)-lysosome interaction are associated with the inhibition of lung cancer cell proliferation by a chloroquinoline analog, Mol Pharmacol
Sugie, Asakura, Zhao, Torita, Nadai et al., Possible involvement of the drug transporters P glycoprotein and multidrug resistance-associated protein Mrp2 in disposition of azithromycin, Antimicrob Agents Chemother
Tan, Yam, Sun, Chu, An evaluation of chloroquine as a broad-acting antiviral against hand, Foot and Mouth Disease, Antiviral Res
Tiberghien, Loor, Ranking of P-glycoprotein substrates and inhibitors by a calcein-AM fluorometry screening assay, Anti-Cancer Drugs
Togami, Chono, Morimoto, Subcellular distribution of azithromycin and clarithromycin in rat alveolar macrophages (NR8383) in vitro, Biol Pharm Bull
Wang, Cao, Zhang, Yang, Liu et al., Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro, Cell Res
Wang, Gomez-Sintes, Boya, Lysosomal membrane permeabilization and cell death, Traffic
Yamagishi, Sahni, Sharp, Jansson, Richardson, P-glycoprotein mediates drug resistance via a novel mechanism involving lysosomal sequestration, J Biol Chem
Yao, Ye, Zhang, Cui, Huang et al., In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Clin Infect Dis,
doi:10.1093/cid/ciaa237
Zhou, Dai, Tong, COVID-19: a recommendation to examine the effect of hydroxychloroquine in preventing infection and progression, J Antimicrob Chemother,
doi:10.1093/jac/dkaa114
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'2011;7(9):1153–67.',
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'unstructured': 'Pene Dumitrescu T, Anic-Milic T, Oreskovic K, Padovan J, Brouwer KL, Zuo '
'P, et al. Development of a population pharmacokinetic model to describe '
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'unstructured': 'Poschet JF, Perkett EA, Timmins GS, Deretic V. Azithromycin and '
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'DOI': '10.1101/2020.03.29.008631'},
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'unstructured': 'Funk RS, Krise JP. Cationic amphiphilic drugs cause a marked expansion '
'of apparent lysosomal volume: implications for an intracellular '
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