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Intracellular ABCB1 as a Possible Mechanism to Explain the Synergistic Effect of Hydroxychloroquine-Azithromycin Combination in COVID-19 Therapy

Scherrmann, AAPS J 22, 86 (2020), doi:10.1208/s12248-020-00465-w
Jun 2020  
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HCQ for COVID-19
1st treatment shown to reduce risk in March 2020, now with p < 0.00000000001 from 418 studies, recognized in 46 countries.
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Proposes a new mechanism supporting the synergistic interaction between HCQ+AZ.
Scherrmann et al., 12 Jun 2020, peer-reviewed, 1 author.
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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.
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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. ' '2019;95(1):127–38.', 'journal-title': 'Mol Pharmacol'}, { 'issue': '9', 'key': '465_CR30', 'doi-asserted-by': 'publisher', 'first-page': '1494', 'DOI': '10.1248/bpb.b13-00423', 'volume': '36', 'author': 'K Togami', 'year': '2013', 'unstructured': 'Togami K, Chono S, Morimoto K. Subcellular distribution of azithromycin ' 'and clarithromycin in rat alveolar macrophages (NR8383) in vitro. Biol ' 'Pharm Bull. 2013;36(9):1494–9.', 'journal-title': 'Biol Pharm Bull'}, { 'issue': '1', 'key': '465_CR31', 'doi-asserted-by': 'publisher', 'first-page': '86', 'DOI': '10.1016/j.ejps.2010.05.016', 'volume': '41', 'author': 'V Munic', 'year': '2010', 'unstructured': 'Munic V, Kelneric Z, Mikac L, Erakovic HV. 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. 2010;41(1):86–95.', 'journal-title': 'Eur J Pharm Sci'}, { 'issue': '7', 'key': '465_CR32', 'doi-asserted-by': 'publisher', 'first-page': '2283', 'DOI': '10.1128/AAC.47.7.2283-2292.2003', 'volume': '47', 'author': 'C Seral', 'year': '2003', 'unstructured': 'Seral C, Van Bambeke F, Tulkens PM. Quantitative analysis of gentamicin, ' 'azithromycin, telithromycin, ciprofloxacin, moxifloxacin, and ' 'oritavancin (LY333328) activities against intracellular Staphylococcus ' 'aureus in mouse J774 macrophages. Antimicrob Agents Chemother. ' '2003;47(7):2283–92.', 'journal-title': 'Antimicrob Agents Chemother'}, { 'issue': '5', 'key': '465_CR33', 'doi-asserted-by': 'publisher', 'first-page': 'e236', 'DOI': '10.1371/journal.pntd.0000236', 'volume': '2', 'author': 'A El-Tahtawy', 'year': '2008', 'unstructured': 'El-Tahtawy A, Glue P, Andrews EN, Mardekian J, Amsden GW, Knirsch CA. ' 'The effect of azithromycin on ivermectin pharmacokinetics--a population ' 'pharmacokinetic model analysis. PLoS Negl Trop Dis. 2008;2(5):e236.', 'journal-title': 'PLoS Negl Trop Dis'}, { 'issue': '5', 'key': '465_CR34', 'doi-asserted-by': 'publisher', 'first-page': '843', 'DOI': '10.1016/S1734-1140(09)70140-9', 'volume': '61', 'author': 'XJ He', 'year': '2009', 'unstructured': 'He XJ, Zhao LM, Qiu F, Sun YX, Li-Ling J. Influence of ABCB1 gene ' 'polymorphisms on the pharmacokinetics of azithromycin among healthy ' 'Chinese Han ethnic subjects. 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Malar J. 2014;13:359.', 'journal-title': 'Malar J'}, { 'issue': '1', 'key': '465_CR43', 'doi-asserted-by': 'publisher', 'first-page': '70', 'DOI': '10.1016/j.ejps.2006.05.009', 'volume': '29', 'author': 'R Hayeshi', 'year': '2006', 'unstructured': 'Hayeshi R, Masimirembwa C, Mukanganyama S, Ungell AL. The potential ' 'inhibitory effect of antiparasitic drugs and natural products on ' 'P-glycoprotein mediated efflux. Eur J Pharm Sci. 2006;29(1):70–81.', 'journal-title': 'Eur J Pharm Sci'}, { 'issue': '5', 'key': '465_CR44', 'doi-asserted-by': 'publisher', 'first-page': '411', 'DOI': '10.1111/j.0954-6820.1982.tb01971.x', 'volume': '211', 'author': 'I Leden', 'year': '1982', 'unstructured': 'Leden I. Digoxin-hydroxychloroquine interaction? 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' 'Drug Metab Rev. 2002;34(1–2):47–54.', 'journal-title': 'Drug Metab Rev'}, { 'key': '465_CR53', 'doi-asserted-by': 'publisher', 'first-page': '749', 'DOI': '10.3389/fphar.2019.00749', 'volume': '10', 'author': 'P Liu-Kreyche', 'year': '2019', 'unstructured': 'Liu-Kreyche P, Shen H, Marino AM, Iyer RA, Humphreys WG, Lai Y. ' 'Lysosomal P-gp-MDR1 confers drug resistance of brentuximab vedotin and ' 'its cytotoxic payload monomethyl auristatin E in tumor cells. Front ' 'Pharmacol. 2019;10:749.', 'journal-title': 'Front Pharmacol'}, { 'issue': '6', 'key': '465_CR54', 'doi-asserted-by': 'publisher', 'first-page': '2593', 'DOI': '10.1073/pnas.1014641108', 'volume': '108', 'author': 'P Kannan', 'year': '2011', 'unstructured': 'Kannan P, Brimacombe KR, Kreisl WC, Liow JS, Zoghbi SS, Telu S, 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. 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