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ISSN (Online): 1873-4251

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Research Article

Suppression of HIV-1 Viral Replication by Inhibiting Drug Efflux Transporters in Activated Macrophages

Author(s): Ying Mu and Theodore J. Cory*

Volume 19, Issue 2, 2021

Published on: 08 October, 2020

Page: [128 - 137] Pages: 10

DOI: 10.2174/1570162X18666201008143833

Price: $65

Abstract

Background: Ethanol has been shown to increase oxidative stress, drug efflux transporter expression, and promote HIV progression. Macrophages, which express drug efflux transporters, serve as an essential sanctuary site for HIV. The antiretroviral drug lopinavir, a protease inhibitor, is a substrate of the drug efflux transporters P-glycoprotein and multidrug resistance-associated protein 1. The NF-κB signaling pathway is associated with inflammation and drug efflux transporter expression.

Objective: To examine the effects of ethanol on drug efflux transporters and HIV replication of macrophages and develop strategies to increase the efficacy of the protease inhibitor.

Methods: The expression of PGP and MRP1 was examined with western blot. The NF- κB inhibition was assessed with nuclear western blot. LC-MS/MS and p24 ELISA were used to assess intracellular LPV and viral replication.

Results: Ethanol at 40mM slightly increased drug efflux transporter PGP and MRP1 expression in activated macrophages. IKK-16, an NF- κB inhibitor, counteracted the increased transporter expression caused by ethanol exposure. MK571, an MRP1 inhibitor, and IKK-16 significantly increased intracellular LPV concentration with or without ethanol treatment. MK571 significantly increased LPV efficacy in suppressing viral replication with or without ethanol treatment. A decreasing trend and a significant decrease were observed with IKK-16+LPV treatment compared with LPV alone in the no ethanol treatment and ethanol treatment groups, respectively.

Conclusion: In activated macrophages, inhibiting drug efflux transporter MRP1 activity and reducing its expression may represent a promising approach to suppress viral replication by increasing intracellular antiretroviral concentrations. However, different strategies may be required for ethanolrelated vs. untreated groups.

Keywords: PGP, MRP1, ethanol, drug efflux transporter inhibition, NF-κB signaling inhibition, intracellular drug concentration, HIV viral replication.

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[1]
WHO. HIV/AIDS Key Facts. 2018.http://www.who.int/news-room/fact-sheets/detail/hiv-aids
[2]
NIH. FDA-Approved HIV Medicines 2018.https://aidsinfo.nih.gov/understanding-hiv-aids/fact-sheets/21/58/fda-approved-hiv-medicines
[3]
Mu Y, Kodidela S, Wang Y, Kumar S, Cory TJ. The dawn of precision medicine in HIV: state of the art of pharmacotherapy. Expert Opin Pharmacother 2018; 19(14): 1581-95.
[http://dx.doi.org/10.1080/14656566.2018.1515916] [PMID: 30234392]
[4]
Gupta RK, Jordan MR, Sultan BJ, et al. Global trends in antiretroviral resistance in treatment-naive individuals with HIV after rollout of antiretroviral treatment in resource-limited settings: a global collaborative study and meta-regression analysis. Lancet 2012; 380(9849): 1250-8.
[http://dx.doi.org/10.1016/S0140-6736(12)61038-1] [PMID: 22828485]
[5]
Rabi SA, Laird GM, Durand CM, et al. Multi-step inhibition explains HIV-1 protease inhibitor pharmacodynamics and resistance. J Clin Invest 2013; 123(9): 3848-60.
[http://dx.doi.org/10.1172/JCI67399] [PMID: 23979165]
[6]
Titanji BK, Aasa-Chapman M, Pillay D, Jolly C. Protease inhibitors effectively block cell-to-cell spread of HIV-1 between T cells. Retrovirology 2013; 10: 161.
[http://dx.doi.org/10.1186/1742-4690-10-161] [PMID: 24364896]
[7]
Howard AA, Arnsten JH, Lo Y, et al. A prospective study of adherence and viral load in a large multi-center cohort of HIV-infected women. AIDS 2002; 16(16): 2175-82.
[http://dx.doi.org/10.1097/00002030-200211080-00010] [PMID: 12409739]
[8]
Miguez MJ, Shor-Posner G, Morales G, Rodriguez A, Burbano X. HIV treatment in drug abusers: impact of alcohol use. Addict Biol 2003; 8(1): 33-7.
[http://dx.doi.org/10.1080/1355621031000069855] [PMID: 12745413]
[9]
Samet JH, Horton NJ, Meli S, Freedberg KA, Palepu A. Alcohol consumption and antiretroviral adherence among HIV-infected persons with alcohol problems. Alcohol Clin Exp Res 2004; 28(4): 572-7.
[http://dx.doi.org/10.1097/01.ALC.0000122103.74491.78] [PMID: 15100608]
[10]
Cook RL, Sereika SM, Hunt SC, Woodward WC, Erlen JA, Conigliaro J. Problem drinking and medication adherence among persons with HIV infection. J Gen Intern Med 2001; 16(2): 83-8.
[http://dx.doi.org/10.1111/j.1525-1497.2001.00122.x] [PMID: 11251758]
[11]
Kapasi AA, Patel G, Goenka A, et al. Ethanol promotes T cell apoptosis through the mitochondrial pathway. Immunology 2003; 108(3): 313-20.
[http://dx.doi.org/10.1046/j.1365-2567.2003.01584.x] [PMID: 12603597]
[12]
Barve SS, Kelkar SV, Gobejishvilli L, Joshi-Barve S, McClain CJ. Mechanisms of alcohol-mediated CD4+ T lymphocyte death: relevance to HIV and HCV pathogenesis. Front Biosci 2002; 7: d1689-96.
[PMID: 12086912]
[13]
Cahill A, Cunningham CC, Adachi M, et al. Effects of alcohol and oxidative stress on liver pathology: the role of the mitochondrion. Alcohol Clin Exp Res 2002; 26(6): 907-15.
[http://dx.doi.org/10.1111/j.1530-0277.2002.tb02621.x] [PMID: 12068261]
[14]
Mansouri A, Fromenty B, Berson A, et al. Multiple hepatic mitochondrial DNA deletions suggest premature oxidative aging in alcoholic patients. J Hepatol 1997; 27(1): 96-102.
[http://dx.doi.org/10.1016/S0168-8278(97)80286-3] [PMID: 9252080]
[15]
Watson RR, Borgs P, Witte M, et al. Alcohol, immunomodulation, and disease. Alcohol Alcohol 1994; 29(2): 131-9.
[PMID: 8080593]
[16]
Jin M, Arya P, Patel K, et al. Effect of alcohol on drug efflux protein and drug metabolic enzymes in U937 macrophages. Alcohol Clin Exp Res 2011; 35(1): 132-9.
[http://dx.doi.org/10.1111/j.1530-0277.2010.01330.x] [PMID: 21039635]
[17]
Günthard HF, Saag MS, Benson CA, et al. Antiretroviral Drugs for Treatment and Prevention of HIV Infection in Adults: 2016 Recommendations of the International Antiviral Society-USA Panel. JAMA 2016; 316(2): 191-210.
[http://dx.doi.org/10.1001/jama.2016.8900] [PMID: 27404187]
[18]
Angelis DS, Tateno AF, Diaz RS, et al. HIV-1 drug resistance genotypic profiles in children with undetectable plasma viremia during antiretroviral therapy. Braz J Infect Dis 2011; 15(1): 60-5.
[http://dx.doi.org/10.1590/S1413-86702011000100011] [PMID: 21412591]
[19]
Ching N, Nielsen-Saines KA, Deville JG, Wei LS, Garratty E, Bryson YJ. Autologous neutralizing antibody to human immunodeficiency virus-1 and replication-competent virus recovered from CD4+ T-cell reservoirs in pediatric HIV-1-infected patients on HAART. AIDS Res Hum Retroviruses 2010; 26(5): 585-91.
[http://dx.doi.org/10.1089/aid.2008.0274] [PMID: 20455762]
[20]
Shan L, Siliciano RF. From reactivation of latent HIV-1 to elimination of the latent reservoir: the presence of multiple barriers to viral eradication. BioEssays 2013; 35(6): 544-52.
[http://dx.doi.org/10.1002/bies.201200170] [PMID: 23613347]
[21]
Finzi D, Hermankova M, Pierson T, et al. Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy. Science 1997; 278(5341): 1295-300.
[http://dx.doi.org/10.1126/science.278.5341.1295] [PMID: 9360927]
[22]
Chavez L, Calvanese V, Verdin E. HIV Latency Is Established Directly and Early in Both Resting and Activated Primary CD4 T Cells. PLoS Pathog 2015; 11(6): e1004955.
[http://dx.doi.org/10.1371/journal.ppat.1004955] [PMID: 26067822]
[23]
Eisele E, Siliciano RF. Redefining the viral reservoirs that prevent HIV-1 eradication. Immunity 2012; 37(3): 377-88.
[http://dx.doi.org/10.1016/j.immuni.2012.08.010] [PMID: 22999944]
[24]
Churchill MJ, Gorry PR, Cowley D, et al. Use of laser capture microdissection to detect integrated HIV-1 DNA in macrophages and astrocytes from autopsy brain tissues. J Neurovirol 2006; 12(2): 146-52.
[http://dx.doi.org/10.1080/13550280600748946] [PMID: 16798676]
[25]
Thompson KA, Cherry CL, Bell JE, McLean CA. Brain cell reservoirs of latent virus in presymptomatic HIV-infected individuals. Am J Pathol 2011; 179(4): 1623-9.
[http://dx.doi.org/10.1016/j.ajpath.2011.06.039] [PMID: 21871429]
[26]
Shen R, Richter HE, Clements RH, et al. Macrophages in vaginal but not intestinal mucosa are monocyte-like and permissive to human immunodeficiency virus type 1 infection. J Virol 2009; 83(7): 3258-67.
[http://dx.doi.org/10.1128/JVI.01796-08] [PMID: 19153236]
[27]
McElrath MJ, Smythe K, Randolph-Habecker J, et al. Comprehensive assessment of HIV target cells in the distal human gut suggests increasing HIV susceptibility toward the anus. J Acquir Immune Defic Syndr 2013; 63(3): 263-71.
[http://dx.doi.org/10.1097/QAI.0b013e3182898392] [PMID: 23392465]
[28]
Cai Y, Sugimoto C, Arainga M, et al. Preferential Destruction of Interstitial Macrophages over Alveolar Macrophages as a Cause of Pulmonary Disease in Simian Immunodeficiency Virus-Infected Rhesus Macaques. J Immunol 2015; 195(10): 4884-91.
[http://dx.doi.org/10.4049/jimmunol.1501194] [PMID: 26432896]
[29]
Abreu CM, Veenhuis RT, Avalos CR, et al. Myeloid and CD4 T Cells Comprise the Latent Reservoir in Antiretroviral Therapy- Suppressed SIVmac251-Infected Macaques. MBio 2019; 10(4): e01659-19.
[http://dx.doi.org/10.1128/mBio.01659-19] [PMID: 31431552]
[30]
Avalos CR, Abreu CM, Queen SE, et al. Brain Macrophages in Simian Immunodeficiency Virus-Infected, Antiretroviral-Suppressed Macaques: a Functional Latent Reservoir. MBio 2017; 8(4): e01186-17.
[http://dx.doi.org/10.1128/mBio.01186-17] [PMID: 28811349]
[31]
Abreu CM, Veenhuis RT, Avalos CR, et al. Infectious Virus Persists in CD4+ T Cells and Macrophages in Antiretroviral Therapy- Suppressed Simian Immunodeficiency Virus-Infected Macaques. J Virol 2019; 93(15): e00065-19.
[http://dx.doi.org/10.1128/JVI.00065-19] [PMID: 31118264]
[32]
Avalos CR, Price SL, Forsyth ER, et al. Quantitation of Productively Infected Monocytes and Macrophages of Simian Immunodeficiency Virus-Infected Macaques. J Virol 2016; 90(12): 5643-56.
[http://dx.doi.org/10.1128/JVI.00290-16] [PMID: 27030272]
[33]
Dallas S, Schlichter L, Bendayan R. Multidrug resistance protein (MRP) 4- and MRP 5-mediated efflux of 9-(2-phosphonylmethoxyethyl) adenine by microglia. J Pharmacol Exp Ther 2004; 309(3): 1221-9.
[http://dx.doi.org/10.1124/jpet.103.063966] [PMID: 14762102]
[34]
Dallas S, Zhu X, Baruchel S, Schlichter L, Bendayan R. Functional expression of the multidrug resistance protein 1 in microglia. J Pharmacol Exp Ther 2003; 307(1): 282-90.
[http://dx.doi.org/10.1124/jpet.103.054304] [PMID: 12893836]
[35]
Jorajuria S, Dereuddre-Bosquet N, Becher F, et al. ATP binding cassette multidrug transporters limit the anti-HIV activity of zidovudine and indinavir in infected human macrophages. Antivir Ther (Lond) 2004; 9(4): 519-28.
[PMID: 15456083]
[36]
Cory TJ, He H, Winchester LC, Kumar S, Fletcher CV. Alterations in p-glycoprotein expression and function between macrophage subsets. Pharm Res 2016; 33(11): 2713-21.
[http://dx.doi.org/10.1007/s11095-016-1998-x] [PMID: 27431863]
[37]
He H, Buckley M, Britton B, et al. Polarized macrophage subsets differentially express the drug efflux transporters MRP1 and BCRP, resulting in altered HIV production. Antivir Chem Chemother 2018; 26: 2040206617745168.
[http://dx.doi.org/10.1177/2040206617745168] [PMID: 29343083]
[38]
Profit L, Eagling VA, Back DJ. Modulation of P-glycoprotein function in human lymphocytes and Caco-2 cell monolayers by HIV-1 protease inhibitors. AIDS 1999; 13(13): 1623-7.
[http://dx.doi.org/10.1097/00002030-199909100-00004] [PMID: 10509562]
[39]
Schuetz JD, Connelly MC, Sun D, et al. MRP4: A previously unidentified factor in resistance to nucleoside-based antiviral drugs. Nat Med 1999; 5(9): 1048-51.
[http://dx.doi.org/10.1038/12487] [PMID: 10470083]
[40]
van der Sandt IC, Vos CM, Nabulsi L, et al. Assessment of active transport of HIV protease inhibitors in various cell lines and the in vitro blood- brain barrier. AIDS 2001; 15(4): 483-91.
[http://dx.doi.org/10.1097/00002030-200103090-00007] [PMID: 11242145]
[41]
Perloff MD, von Moltke LL, Greenblatt DJ. Fexofenadine transport in Caco-2 cells: inhibition with verapamil and ritonavir. J Clin Pharmacol 2002; 42(11): 1269-74.
[http://dx.doi.org/10.1177/009127002762491370] [PMID: 12412827]
[42]
Zastre JA, Chan GN, Ronaldson PT, et al. Up-regulation of P-glycoprotein by HIV protease inhibitors in a human brain microvessel endothelial cell line. J Neurosci Res 2009; 87(4): 1023-36.
[http://dx.doi.org/10.1002/jnr.21898] [PMID: 18855943]
[43]
Storch CH, Theile D, Lindenmaier H, Haefeli WE, Weiss J. Comparison of the inhibitory activity of anti-HIV drugs on P-glycoprotein. Biochem Pharmacol 2007; 73(10): 1573-81.
[http://dx.doi.org/10.1016/j.bcp.2007.01.027] [PMID: 17328866]
[44]
Bousquet L, Roucairol C, Hembury A, et al. Comparison of ABC transporter modulation by atazanavir in lymphocytes and human brain endothelial cells: ABC transporters are involved in the atazanavir-limited passage across an in vitro human model of the blood-brain barrier. AIDS Res Hum Retroviruses 2008; 24(9): 1147-54.
[http://dx.doi.org/10.1089/aid.2007.0022] [PMID: 18729774]
[45]
Boé DM, Richens TR, Horstmann SA, et al. Acute and chronic alcohol exposure impair the phagocytosis of apoptotic cells and enhance the pulmonary inflammatory response. Alcohol Clin Exp Res 2010; 34(10): 1723-32.
[http://dx.doi.org/10.1111/j.1530-0277.2010.01259.x] [PMID: 20608904]
[46]
Baum MK, Rafie C, Lai S, Sales S, Page JB, Campa A. Alcohol use accelerates HIV disease progression. AIDS Res Hum Retroviruses 2010; 26(5): 511-8.
[http://dx.doi.org/10.1089/aid.2009.0211] [PMID: 20455765]
[47]
Neuman MG, Schneider M, Nanau RM, Parry C. Alcohol Consumption, Progression of Disease and Other Comorbidities, and Responses to Antiretroviral Medication in People Living with HIV. Aids Res Treat 2012; 2012: 751827.
[http://dx.doi.org/10.1155/2012/751827] [PMID: 22496971]
[48]
Enomoto N, Ikejima K, Yamashina S, et al. Kupffer cell sensitization by alcohol involves increased permeability to gut-derived endotoxin. Alcohol Clin Exp Res 2001; 25(6)(Suppl.): 51S-4S.
[http://dx.doi.org/10.1111/j.1530-0277.2001.tb02418.x] [PMID: 11410742]
[49]
Wang F, Yang JL, Yu KK, et al. Activation of the NF-κB pathway as a mechanism of alcohol enhanced progression and metastasis of human hepatocellular carcinoma. Mol Cancer 2015; 14: 10.
[http://dx.doi.org/10.1186/s12943-014-0274-0] [PMID: 25622857]
[50]
Wang Y, Liu X, Zhang HT, Yu M, Wang H. [NF-kappaB regulating expression of mdr1 gene and P-gp to reverse drug-resistance in leukemic cells]. Zhongguo Shi Yan Xue Ye Xue Za Zhi 2007; 15(5): 950-4.
[PMID: 17956668]
[51]
Fujioka S, Niu J, Schmidt C, et al. NF-kappaB and AP-1 connection: mechanism of NF-kappaB-dependent regulation of AP-1 activity. Mol Cell Biol 2004; 24(17): 7806-19.
[http://dx.doi.org/10.1128/MCB.24.17.7806-7819.2004] [PMID: 15314185]
[52]
Olefsky JM, Glass CK. Macrophages, inflammation, and insulin resistance. Annu Rev Physiol 2010; 72: 219-46.
[http://dx.doi.org/10.1146/annurev-physiol-021909-135846] [PMID: 20148674]
[53]
Tobias PS, Soldau K, Ulevitch RJ. Identification of a lipid A binding site in the acute phase reactant lipopolysaccharide binding protein. J Biol Chem 1989; 264(18): 10867-71.
[PMID: 2471708]
[54]
Poltorak A, He X, Smirnova I, et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 1998; 282(5396): 2085-8.
[http://dx.doi.org/10.1126/science.282.5396.2085] [PMID: 9851930]
[55]
Ronaldson PT, Ashraf T, Bendayan R. Regulation of multidrug resistance protein 1 by tumor necrosis factor alpha in cultured glial cells: involvement of nuclear factor-kappaB and c-Jun N-terminal kinase signaling pathways. Mol Pharmacol 2010; 77(4): 644-59.
[http://dx.doi.org/10.1124/mol.109.059410] [PMID: 20051532]
[56]
Zhang R, Lu M, Zhang Z, Tian X, Wang S, Lv D. Resveratrol reverses P-glycoprotein-mediated multidrug resistance of U2OS/ADR cells by suppressing the activation of the NF-κB and p38 MAPK signaling pathways. Oncol Lett 2016; 12(5): 4147-54.
[http://dx.doi.org/10.3892/ol.2016.5136] [PMID: 27895784]
[57]
Wang X, Huang S, Jiang Y, et al. Reactive astrocytes increase the expression of P-gp and Mrp1 via TNF-α and NF-κB signaling. Mol Med Rep 2018; 17(1): 1198-204.
[PMID: 29115482]
[58]
Velaei K, Samadi N, Soltani S, Barazvan B, Soleimani Rad J. NFκBP65 transcription factor modulates resistance to doxorubicin through ABC transporters in breast cancer. Breast Cancer 2017; 24(4): 552-61.
[http://dx.doi.org/10.1007/s12282-016-0738-8] [PMID: 27878697]
[59]
Chang MS, Chen BC, Yu MT, Sheu JR, Chen TF, Lin CH. Phorbol 12-myristate 13-acetate upregulates cyclooxygenase-2 expression in human pulmonary epithelial cells via Ras, Raf-1, ERK, and NF-kappaB, but not p38 MAPK, pathways. Cell Signal 2005; 17(3): 299-310.
[http://dx.doi.org/10.1016/j.cellsig.2004.07.008] [PMID: 15567061]
[60]
Choi JY, Song YG, Kim YH, et al. Factors associated with HIV-1 proviral DNA loads in patients with undetectable plasma RNA load. J Korean Med Sci 2009; 24(1): 152-4.
[http://dx.doi.org/10.3346/jkms.2009.24.1.152] [PMID: 19270829]
[61]
Natarajan V, Bosche M, Metcalf JA, Ward DJ, Lane HC, Kovacs JA. HIV-1 replication in patients with undetectable plasma virus receiving HAART. Highly active antiretroviral therapy. Lancet 1999; 353(9147): 119-20.
[http://dx.doi.org/10.1016/S0140-6736(05)76156-0] [PMID: 10023903]
[62]
Buzón MJ, Codoñer FM, Frost SD, et al. Deep molecular characterization of HIV-1 dynamics under suppressive HAART. PLoS Pathog 2011; 7(10): e1002314.
[http://dx.doi.org/10.1371/journal.ppat.1002314] [PMID: 22046128]
[63]
Sharkey ME, Teo I, Greenough T, et al. Persistence of episomal HIV-1 infection intermediates in patients on highly active anti-retroviral therapy. Nat Med 2000; 6(1): 76-81.
[http://dx.doi.org/10.1038/71569] [PMID: 10613828]
[64]
Cory TJ, Schacker TW, Stevenson M, Fletcher CV. Overcoming pharmacologic sanctuaries. Curr Opin HIV AIDS 2013; 8(3): 190-5.
[http://dx.doi.org/10.1097/COH.0b013e32835fc68a] [PMID: 23454865]
[65]
Di Mascio M, Srinivasula S, Bhattacharjee A, et al. Antiretroviral tissue kinetics: in vivo imaging using positron emission tomography. Antimicrob Agents Chemother 2009; 53(10): 4086-95.
[http://dx.doi.org/10.1128/AAC.00419-09] [PMID: 19667288]
[66]
Honeycutt JB, Thayer WO, Baker CE, et al. HIV persistence in tissue macrophages of humanized myeloid-only mice during antiretroviral therapy. Nat Med 2017; 23(5): 638-43.
[http://dx.doi.org/10.1038/nm.4319] [PMID: 28414330]
[67]
Kumar A, Herbein G. The macrophage: a therapeutic target in HIV-1 infection. Mol Cell Ther 2014; 2: 10.
[http://dx.doi.org/10.1186/2052-8426-2-10] [PMID: 26056579]
[68]
Ansbro MR, Shukla S, Ambudkar SV, Yuspa SH, Li L. Screening compounds with a novel high-throughput ABCB1-mediated efflux assay identifies drugs with known therapeutic targets at risk for multidrug resistance interference. PLoS One 2013; 8(4): e60334.
[http://dx.doi.org/10.1371/journal.pone.0060334] [PMID: 23593196]
[69]
Stoltz DA, Nelson S, Kolls JK, et al. In vitro ethanol suppresses alveolar macrophage TNF-alpha during simian immunodeficiency virus infection. Am J Respir Crit Care Med 2000; 161(1): 135-40.
[http://dx.doi.org/10.1164/ajrccm.161.1.9905016] [PMID: 10619810]
[70]
Osborn L, Kunkel S, Nabel GJ. Tumor necrosis factor alpha and interleukin 1 stimulate the human immunodeficiency virus enhancer by activation of the nuclear factor kappa B. Proc Natl Acad Sci USA 1989; 86(7): 2336-40.
[http://dx.doi.org/10.1073/pnas.86.7.2336] [PMID: 2494664]
[71]
Heemskerk S, Peters JG, Louisse J, Sagar S, Russel FG, Masereeuw R. Regulation of P-glycoprotein in renal proximal tubule epithelial cells by LPS and TNF-alpha. J Biomed Biotechnol 2010; 2010: 525180.
[http://dx.doi.org/10.1155/2010/525180] [PMID: 20300455]
[72]
Lv Z, Chu Y, Wang Y. HIV protease inhibitors: a review of molecular selectivity and toxicity. HIV AIDS (Auckl) 2015; 7: 95-104.
[PMID: 25897264]
[73]
Martinez MN, Amidon GL. A mechanistic approach to understanding the factors affecting drug absorption: a review of fundamentals. J Clin Pharmacol 2002; 42(6): 620-43.
[http://dx.doi.org/10.1177/00970002042006005] [PMID: 12043951]
[74]
Midde NM, Sinha N, Lukka PB, Meibohm B, Kumar S. Alterations in cellular pharmacokinetics and pharmacodynamics of elvitegravir in response to ethanol exposure in HIV-1 infected monocytic (U1) cells. PLoS One 2017; 12(2): e0172628.
[http://dx.doi.org/10.1371/journal.pone.0172628] [PMID: 28231276]
[75]
Romeo R, Iannazzo D, Veltri L, et al. Pyrimidine 2,4-Diones in the Design of New HIV RT Inhibitors. Molecules 2019; 24(9): E1718.
[http://dx.doi.org/10.3390/molecules24091718] [PMID: 31052607]
[76]
Flefel EM, El-Sofany WI, El-Shahat M, Naqvi A, Assirey E. Synthesis, molecular docking and in vitro screening of some newly synthesized triazolopyridine, pyridotriazine and pyridine-pyrazole hybrid derivatives. Molecules 2018; 23(10): E2548.
[http://dx.doi.org/10.3390/molecules23102548] [PMID: 30301217]
[77]
Flefel EM, Tantawy WA, El-Sofany WI, El-Shahat M, El-Sayed AA, Abd-Elshafy DN. Synthesis of Some New Pyridazine Derivatives for Anti-HAV Evaluation. Molecules 2017; 22(1): E148.
[http://dx.doi.org/10.3390/molecules22010148] [PMID: 28106751]

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