{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T15:41:13Z","timestamp":1787067673447,"version":"build-2736575974"},"reference-count":84,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2022,2,18]],"date-time":"2022-02-18T00:00:00Z","timestamp":1645142400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001824","name":"Czech Science Foundation","doi-asserted-by":"publisher","award":["18-443 07281Y"],"award-info":[{"award-number":["18-443 07281Y"]}],"id":[{"id":"10.13039\/501100001824","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007397","name":"Charles University","doi-asserted-by":"publisher","award":["GAUK 364521"],"award-info":[{"award-number":["GAUK 364521"]}],"id":[{"id":"10.13039\/100007397","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007397","name":"Charles University","doi-asserted-by":"publisher","award":["SVV 260 549"],"award-info":[{"award-number":["SVV 260 549"]}],"id":[{"id":"10.13039\/100007397","id-type":"DOI","asserted-by":"publisher"}]},{"name":"EFSA - CDN","award":["CZ.02.1.01\/0.0\/0.0\/16_019\/0000841"],"award-info":[{"award-number":["CZ.02.1.01\/0.0\/0.0\/16_019\/0000841"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>The inhibition of P-glycoprotein (ABCB1) could lead to increased drug plasma concentrations and hence increase drug toxicity. The evaluation of a drug\u2019s ability to inhibit ABCB1 is complicated by the presence of several transport-competent sites within the ABCB1 binding pocket, making it difficult to select appropriate substrates. Here, we investigate the capacity of antiretrovirals and direct-acting antivirals to inhibit the ABCB1-mediated intestinal efflux of [3H]-digoxin and compare it with our previous rhodamine123 study. At concentrations of up to 100 \u00b5M, asunaprevir, atazanavir, daclatasvir, darunavir, elbasvir, etravirine, grazoprevir, ledipasvir, lopinavir, rilpivirine, ritonavir, saquinavir, and velpatasvir inhibited [3H]-digoxin transport in Caco-2 cells and\/or in precision-cut intestinal slices prepared from the human jejunum (hPCIS). However, abacavir, dolutegravir, maraviroc, sofosbuvir, tenofovir disoproxil fumarate, and zidovudine had no inhibitory effect. We thus found that most of the tested antivirals have a high potential to cause drug\u2013drug interactions on intestinal ABCB1. Comparing the Caco-2 and hPCIS experimental models, we conclude that the Caco-2 transport assay is more sensitive, but the results obtained using hPCIS agree better with reported in vivo observations. More inhibitors were identified when using digoxin as the ABCB1 probe substrate than when using rhodamine123. However, both approaches had limitations, indicating that inhibitory potency should be tested with at least these two ABCB1 probes.<\/jats:p>","DOI":"10.3390\/ph15020242","type":"journal-article","created":{"date-parts":[[2022,2,21]],"date-time":"2022-02-21T08:23:29Z","timestamp":1645431809000},"page":"242","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Evaluation of the Potency of Anti-HIV and Anti-HCV Drugs to Inhibit P-Glycoprotein Mediated Efflux of Digoxin in Caco-2 Cell Line and Human Precision-Cut Intestinal Slices"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6233-9224","authenticated-orcid":false,"given":"Martin","family":"Huli\u010diak","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Kr\u00e1lov\u00e9, Charles University, 50005 Hradec Kr\u00e1lov\u00e9, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1348-0395","authenticated-orcid":false,"given":"Ivan","family":"Vok\u0159\u00e1l","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Kr\u00e1lov\u00e9, Charles University, 50005 Hradec Kr\u00e1lov\u00e9, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8335-0123","authenticated-orcid":false,"given":"Ond\u0159ej","family":"Holas","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Technology, Faculty of Pharmacy in Hradec Kr\u00e1lov\u00e9, Charles University, 50005 Hradec Kr\u00e1lov\u00e9, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5661-6312","authenticated-orcid":false,"given":"Ond\u0159ej","family":"Martinec","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Kr\u00e1lov\u00e9, Charles University, 50005 Hradec Kr\u00e1lov\u00e9, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franti\u0161ek","family":"\u0160taud","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Kr\u00e1lov\u00e9, Charles University, 50005 Hradec Kr\u00e1lov\u00e9, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1313-306X","authenticated-orcid":false,"given":"Luk\u00e1\u0161","family":"\u010cerven\u00fd","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Kr\u00e1lov\u00e9, Charles University, 50005 Hradec Kr\u00e1lov\u00e9, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,2,18]]},"reference":[{"key":"ref_1","unstructured":"WHO (2021, July 17). HIV\/AIDS. Available online: www.who.int\/news-room\/fact-sheets\/detail\/hiv-aids."},{"key":"ref_2","unstructured":"WHO (2021, July 17). Hepatitis C. Available online: http:\/\/www.who.int\/news-room\/fact-sheets\/detail\/hepatitis-c."},{"key":"ref_3","unstructured":"WHO (2021, July 17). Global Hepatitis Report. Available online: https:\/\/apps.who.int\/iris\/bitstream\/handle\/10665\/255016\/9789?sequence=1."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2165","DOI":"10.1097\/QAD.0b013e32801022eb","article-title":"Antiretroviral therapy and the prevalence of osteopenia and osteoporosis: A meta-analytic review","volume":"20","author":"Brown","year":"2006","journal-title":"AIDS"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2244","DOI":"10.2337\/dc10-0633","article-title":"Association between systemic inflammation and incident diabetes in HIV-infected patients after initiation of antiretroviral therapy","volume":"33","author":"Brown","year":"2010","journal-title":"Diabetes Care"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1387","DOI":"10.1097\/QAD.0b013e32836010bd","article-title":"Elevated sCD163 in plasma but not cerebrospinal fluid is a marker of neurocognitive impairment in HIV infection","volume":"27","author":"Burdo","year":"2013","journal-title":"AIDS"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1016\/j.atherosclerosis.2009.05.001","article-title":"Lipoprotein particle subclasses, cardiovascular disease and HIV infection","volume":"207","author":"Duprez","year":"2009","journal-title":"Atherosclerosis"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2158","DOI":"10.1002\/jmv.24848","article-title":"Comorbidities and medications of patients with chronic hepatitis C under specialist care in the UK","volume":"89","author":"Hudson","year":"2017","journal-title":"J. Med. Virol."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Louie, K.S., St Laurent, S., Forssen, U.M., Mundy, L.M., and Pimenta, J.M. (2012). The high comorbidity burden of the hepatitis C virus infected population in the United States. BMC Infect. Dis., 12.","DOI":"10.1186\/1471-2334-12-86"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1097\/QAI.0b013e3181b327ca","article-title":"A meta-analysis of the incidence of non-AIDS cancers in HIV-infected individuals","volume":"52","author":"Shiels","year":"2009","journal-title":"J. Acquir. Immune Defic. Syndr."},{"key":"ref_11","unstructured":"Department of Health and Human Services (2020, August 26). Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV, Available online: https:\/\/clinicalinfo.hiv.gov\/sites\/default\/files\/guidelines\/documents\/AdultandAdolescentGL.pdf."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1017\/S109285291800113X","article-title":"Drug-drug interactions and clinical considerations with co-administration of antiretrovirals and psychotropic drugs","volume":"24","author":"Goodlet","year":"2019","journal-title":"CNS Spectr."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"413","DOI":"10.3851\/IMP1540","article-title":"Prevalence of comedications and effect of potential drug-drug interactions in the Swiss HIV Cohort Study","volume":"15","author":"Marzolini","year":"2010","journal-title":"Antivir. Ther."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"S39","DOI":"10.1097\/QAD.0b013e32835584ea","article-title":"Antiretroviral therapy adherence and drug-drug interactions in the aging HIV population","volume":"26","author":"Nachega","year":"2012","journal-title":"AIDS"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1111\/bcp.13095","article-title":"Managing drug-drug interactions with new direct-acting antiviral agents in chronic hepatitis C","volume":"83","author":"Boyer","year":"2017","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"166206","DOI":"10.1016\/j.bbadis.2021.166206","article-title":"HIV in pregnancy: Mother-to-child transmission, pharmacotherapy, and toxicity","volume":"1867","author":"Cerveny","year":"2021","journal-title":"Biochim Biophys. Acta Mol. Basis Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1007\/s40121-015-0061-2","article-title":"Drug-Drug Interactions Among Hepatitis C Virus (HCV) and Human Immunodeficiency Virus (HIV) Medications","volume":"4","author":"Kaur","year":"2015","journal-title":"Infect. Dis. Ther."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.tips.2009.10.001","article-title":"The complexities of antiretroviral drug-drug interactions: Role of ABC and SLC transporters","volume":"31","author":"Kis","year":"2010","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"836","DOI":"10.1002\/cpt.1216","article-title":"Clinical Probes and Endogenous Biomarkers as Substrates for Transporter Drug-Drug Interaction Evaluation: Perspectives From the International Transporter Consortium","volume":"104","author":"Chu","year":"2018","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.ejps.2018.04.039","article-title":"New insights in the in vitro characterisation and molecular modelling of the P-glycoprotein inhibitory promiscuity","volume":"121","author":"Bocci","year":"2018","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Jouan, E., Le Vee, M., Mayati, A., Denizot, C., Parmentier, Y., and Fardel, O. (2016). Evaluation of P-Glycoprotein Inhibitory Potential Using a Rhodamine 123 Accumulation Assay. Pharmaceutics, 8.","DOI":"10.3390\/pharmaceutics8020012"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.bcp.2016.10.002","article-title":"Location of contact residues in pharmacologically distinct drug binding sites on P-glycoprotein","volume":"123","author":"Mittra","year":"2017","journal-title":"Biochem. Pharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1111\/j.1365-2125.2012.04453.x","article-title":"Oral bioavailability of dabigatran etexilate (Pradaxa((R)) ) after co-medication with verapamil in healthy subjects","volume":"75","author":"Hartter","year":"2013","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1334","DOI":"10.1124\/dmd.109.026591","article-title":"Intestinal perfusion with mesenteric blood sampling in wild-type and knockout mice: Evaluation of a novel tool in biopharmaceutical drug profiling","volume":"37","author":"Mols","year":"2009","journal-title":"Drug Metab. Dispos."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1067\/mcp.2000.107579","article-title":"Oral bioavailability of digoxin is enhanced by talinolol: Evidence for involvement of intestinal P-glycoprotein","volume":"68","author":"Westphal","year":"2000","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"161","DOI":"10.5414\/CPP38161","article-title":"P-glycoprotein inhibitor erythromycin increases oral bioavailability of talinolol in humans","volume":"38","author":"Schwarz","year":"2000","journal-title":"Int. J. Clin. Pharmacol. Ther."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1111\/j.1365-2125.2009.03396.x","article-title":"Enantioselective disposition of fexofenadine with the P-glycoprotein inhibitor verapamil","volume":"67","author":"Sakugawa","year":"2009","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e01201-17","DOI":"10.1128\/AAC.01201-17","article-title":"Differential Influence of the Antiretroviral Pharmacokinetic Enhancers Ritonavir and Cobicistat on Intestinal P-Glycoprotein Transport and the Pharmacokinetic\/Pharmacodynamic Disposition of Dabigatran","volume":"61","author":"Kumar","year":"2017","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1182","DOI":"10.1002\/cpt.1073","article-title":"Cytochrome P450 3A Induction Predicts P-glycoprotein Induction; Part 1: Establishing Induction Relationships Using Ascending Dose Rifampin","volume":"104","author":"Lutz","year":"2018","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1191","DOI":"10.1002\/cpt.1072","article-title":"Cytochrome P450 3A Induction Predicts P-glycoprotein Induction; Part 2: Prediction of Decreased Substrate Exposure After Rifabutin or Carbamazepine","volume":"104","author":"Lutz","year":"2018","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1111\/j.1365-2125.2012.04218.x","article-title":"Decrease in the oral bioavailability of dabigatran etexilate after co-medication with rifampicin","volume":"74","author":"Hartter","year":"2012","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1540","DOI":"10.1038\/nprot.2010.111","article-title":"Preparation and incubation of precision-cut liver and intestinal slices for application in drug metabolism and toxicity studies","volume":"5","author":"Olinga","year":"2010","journal-title":"Nat. Protoc."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1517\/17425255.2016.1125882","article-title":"Precision-cut intestinal slices: Alternative model for drug transport, metabolism, and toxicology research","volume":"12","author":"Li","year":"2016","journal-title":"Expert Opin. Drug Metab. Protoc."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1128\/AAC.00910-19","article-title":"Anti-HIV and Anti-Hepatitis C Virus Drugs Inhibit P-Glycoprotein Efflux Activity in Caco-2 Cells and Precision-Cut Rat and Human Intestinal Slices","volume":"63","author":"Martinec","year":"2019","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1002\/bdd.2047","article-title":"P-gp activity and inhibition in the different regions of human intestine ex vivo","volume":"38","author":"Li","year":"2017","journal-title":"Biopharm. Drug Dispos."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Forster, S., Thumser, A.E., Hood, S.R., and Plant, N. (2012). Characterization of rhodamine-123 as a tracer dye for use in in vitro drug transport assays. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0033253"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1573","DOI":"10.1016\/j.bcp.2007.01.027","article-title":"Comparison of the inhibitory activity of anti-HIV drugs on P-glycoprotein","volume":"73","author":"Storch","year":"2007","journal-title":"Biochem. Pharmacol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1124\/dmd.105.008615","article-title":"In vitro p-glycoprotein inhibition assays for assessment of clinical drug interaction potential of new drug candidates: A recommendation for probe substrates","volume":"34","author":"Rautio","year":"2006","journal-title":"Drug Metab. Dispos."},{"key":"ref_39","unstructured":"FDA (2021, September 10). Drug Development and Drug Interactions|Table of Substrates, Inhibitors and Inducers, Available online: https:\/\/www.fda.gov\/drugs\/drug-interactions-labeling\/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers#table1."},{"key":"ref_40","unstructured":"EMA (2021, September 10). Guideline on the Investigation of Drug Interactions. Available online: https:\/\/www.ema.europa.eu\/documents\/scientific-guideline\/guideline-investigation-drug-interactions_en.pdf."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1016\/j.jep.2012.10.001","article-title":"P-glycoprotein mediated efflux in Caco-2 cell monolayers: The influence of herbals on digoxin transport","volume":"144","author":"Oga","year":"2012","journal-title":"J. EthnoPharmacol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1212","DOI":"10.1124\/dmd.117.079038","article-title":"The Drug-Drug Interaction Potential of Antiviral Agents for the Treatment of Chronic Hepatitis C Infection","volume":"46","author":"Garrison","year":"2018","journal-title":"Drug Metab. Dispos."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Poizot-Martin, I., Naqvi, A., Obry-Roguet, V., Valantin, M.A., Cuzin, L., Billaud, E., Cheret, A., Rey, D., Jacomet, C., and Duvivier, C. (2015). Potential for Drug-Drug Interactions between Antiretrovirals and HCV Direct Acting Antivirals in a Large Cohort of HIV\/HCV Coinfected Patients. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0141164"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1007\/s40261-020-00962-y","article-title":"Drug-Drug Interactions between Direct Oral Anticoagulants and Hepatitis C Direct-Acting Antiviral Agents: Looking for Evidence Through a Systematic Review","volume":"40","author":"Bellesini","year":"2020","journal-title":"Clin. Drug Investig."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"6089","DOI":"10.1038\/s41598-021-85586-8","article-title":"Potential drug-drug interactions of antiretrovirals and antimicrobials detected by three databases","volume":"11","author":"Vivithanaporn","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"322","DOI":"10.14218\/JCTH.2020.00034","article-title":"Review of Clinically Relevant Drug Interactions with Next Generation Hepatitis C Direct-acting Antiviral Agents","volume":"8","author":"Hong","year":"2020","journal-title":"J. Clin. Transl. Hepatol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1038\/nrd3028","article-title":"Membrane transporters in drug development","volume":"9","author":"Giacomini","year":"2010","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2093","DOI":"10.1124\/dmd.111.040816","article-title":"Digoxin is not a substrate for organic anion-transporting polypeptide transporters OATP1A2, OATP1B1, OATP1B3, and OATP2B1 but is a substrate for a sodium-dependent transporter expressed in HEK293 cells","volume":"39","author":"Taub","year":"2011","journal-title":"Drug Metab. Dispos."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1","DOI":"10.2174\/1568011043482142","article-title":"Identification and characterization of the binding sites of P-glycoprotein for multidrug resistance-related drugs and modulators","volume":"4","author":"Safa","year":"2004","journal-title":"Curr. Med. Chem.-Anti-Cancer Agents"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1124\/dmd.116.072231","article-title":"Regional Expression Levels of Drug Transporters and Metabolizing Enzymes along the Pig and Human Intestinal Tract and Comparison with Caco-2 Cells","volume":"45","author":"Vaessen","year":"2017","journal-title":"Drug Metab. Dispos."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1016\/j.ejps.2006.04.010","article-title":"Regional levels of drug transporters along the human intestinal tract: Co-expression of ABC and SLC transporters and comparison with Caco-2 cells","volume":"29","author":"Englund","year":"2006","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1138","DOI":"10.1111\/j.1440-1681.2007.04691.x","article-title":"Expression of CYP3A isoforms and P-glycoprotein in human stomach, jejunum and ileum","volume":"34","author":"Canaparo","year":"2007","journal-title":"Clin. Exp. Pharmacol. Physiol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1588","DOI":"10.1248\/bpb.32.1588","article-title":"P-glycoprotein mediates efflux transport of darunavir in human intestinal Caco-2 and ABCB1 gene-transfected renal LLC-PK1 cell lines","volume":"32","author":"Fujimoto","year":"2009","journal-title":"Biol. Pharm. Bull."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1672","DOI":"10.1093\/jac\/dkq209","article-title":"Protease inhibitors atazanavir, lopinavir and ritonavir are potent blockers, but poor substrates, of ABC transporters in a broad panel of ABC transporter-overexpressing cell lines","volume":"65","author":"Bierman","year":"2010","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"3757","DOI":"10.21873\/anticanres.13524","article-title":"Co-treatment With HIV Protease Inhibitor Nelfinavir Greatly Increases Late-phase Apoptosis of Drug-resistant KBV20C Cancer Cells Independently of P-Glycoprotein Inhibition","volume":"39","author":"Kim","year":"2019","journal-title":"Anticancer Res."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1092","DOI":"10.1097\/00002030-200305020-00023","article-title":"Lopinavir: Acute exposure inhibits P-glycoprotein; extended exposure induces P-glycoprotein","volume":"17","author":"Vishnuvardhan","year":"2003","journal-title":"AIDS"},{"key":"ref_57","first-page":"87","article-title":"Clinical perspective on drug-drug interactions with the non-nucleoside reverse transcriptase inhibitor rilpivirine","volume":"15","author":"Crauwels","year":"2013","journal-title":"AIDS Rev."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1282","DOI":"10.1128\/AAC.01527-10","article-title":"Interaction potential of etravirine with drug transporters assessed in vitro","volume":"55","author":"Zembruski","year":"2011","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_59","unstructured":"Janssen Therapeutics (2021, November 02). Intelence. Available online: https:\/\/www.janssenlabels.com\/package-insert\/product-monograph\/prescribing-information\/INTELENCE-pi.pdf."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1124\/dmd.112.048918","article-title":"In vitro investigations into the roles of drug transporters and metabolizing enzymes in the disposition and drug interactions of dolutegravir, a HIV integrase inhibitor","volume":"41","author":"Reese","year":"2013","journal-title":"Drug Metab. Dispos."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1097\/QAD.0000000000000112","article-title":"Interactions of tenofovir and tenofovir disoproxil fumarate with drug efflux transporters ABCB1, ABCG2, and ABCC2; role in transport across the placenta","volume":"28","author":"Neumanova","year":"2014","journal-title":"AIDS"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1002\/bdd.1993","article-title":"Role of ABCB1, ABCG2, ABCC2 and ABCC5 transporters in placental passage of zidovudine","volume":"37","author":"Neumanova","year":"2016","journal-title":"Biopharm. Drug Dispos."},{"key":"ref_63","first-page":"176","article-title":"Effect of drug efflux transporters on placental transport of antiretroviral agent abacavir","volume":"57","author":"Neumanova","year":"2015","journal-title":"Reprod. Protoc."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"26245","DOI":"10.1073\/pnas.2010264117","article-title":"Cryo-EM structures reveal distinct mechanisms of inhibition of the human multidrug transporter ABCB1","volume":"117","author":"Nosol","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"2813","DOI":"10.1002\/jps.24356","article-title":"Preclinical Pharmacokinetics and In Vitro Metabolism of Asunaprevir (BMS-650032), a Potent Hepatitis C Virus NS3 Protease Inhibitor","volume":"104","author":"Mosure","year":"2015","journal-title":"J. Pharm. Sci."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1007\/s40268-017-0222-8","article-title":"Effects of a Fixed-Dose Co-Formulation of Daclatasvir, Asunaprevir, and Beclabuvir on the Pharmacokinetics of a Cocktail of Cytochrome P450 and Drug Transporter Substrates in Healthy Subjects","volume":"18","author":"Garimella","year":"2018","journal-title":"Drugs R&D"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1007\/s40262-015-0334-7","article-title":"Use of Multiple Probes to Assess Transporter- and Cytochrome P450-Mediated Drug-Drug Interaction Potential of the Pangenotypic HCV NS5A Inhibitor Velpatasvir","volume":"55","author":"Mogalian","year":"2016","journal-title":"Clin. Pharm."},{"key":"ref_68","unstructured":"Merck Sharp & Dohme Corp (2021, November 09). Zepatier, Available online: https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2017\/208261s002lbl.pdf."},{"key":"ref_69","first-page":"164","article-title":"Correlation of gene expression of ten drug efflux proteins of the ATP-binding cassette transporter family in normal human jejunum and in human intestinal epithelial Caco-2 cell monolayers","volume":"299","author":"Taipalensuu","year":"2001","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1038\/clpt.2013.81","article-title":"In vitro methods to support transporter evaluation in drug discovery and development","volume":"94","author":"Brouwer","year":"2013","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1517\/17425255.4.4.395","article-title":"The Caco-2 cell monolayer: Usefulness and limitations","volume":"4","author":"Sun","year":"2008","journal-title":"Expert Opin. Drug Metab. Protoc."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"745","DOI":"10.3390\/pharmaceutics3040745","article-title":"Antiretroviral drug interactions: Overview of interactions involving new and investigational agents and the role of therapeutic drug monitoring for management","volume":"3","author":"Rathbun","year":"2011","journal-title":"Pharmaceutics"},{"key":"ref_73","first-page":"376","article-title":"Characterization of the major metabolites of verapamil as substrates and inhibitors of P-glycoprotein","volume":"293","author":"Burk","year":"2000","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1002\/bdd.2025","article-title":"Caco-2 cells\u2014Expression, regulation and function of drug transporters compared with human jejunal tissue","volume":"38","author":"Bruck","year":"2017","journal-title":"Biopharm. Drug Dispos."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1002\/cpdd.91","article-title":"The effect of maraviroc on the pharmacokinetics of digoxin in healthy volunteers","volume":"3","author":"Vourvahis","year":"2014","journal-title":"Clin. Pharmacol. Drug Dev."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"4914","DOI":"10.1002\/jps.21756","article-title":"N-(3,4-dimethoxyphenethyl)-4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2[1H]-yl)-6,7-dimethoxyquinazolin-2-amine (CP-100,356) as a \u201cchemical knock-out equivalent\u201d to assess the impact of efflux transporters on oral drug absorption in the rat","volume":"98","author":"Kalgutkar","year":"2009","journal-title":"J. Pharm. Sci."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"684156","DOI":"10.3389\/fphar.2021.684156","article-title":"Rifampicin Induces Gene, Protein, and Activity of P-Glycoprotein (ABCB1) in Human Precision-Cut Intestinal Slices","volume":"12","author":"Martinec","year":"2021","journal-title":"Front. Pharmacol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1016\/j.ejpb.2012.07.020","article-title":"Comparison of brain capillary endothelial cell-based and epithelial (MDCK-MDR1, Caco-2, and VB-Caco-2) cell-based surrogate blood-brain barrier penetration models","volume":"82","author":"Hellinger","year":"2012","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"764","DOI":"10.1124\/dmd.104.002931","article-title":"Atazanavir: Effects on P-glycoprotein transport and CYP3A metabolism in vitro","volume":"33","author":"Perloff","year":"2005","journal-title":"Drug Metab. Dispos."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"2111","DOI":"10.1038\/nprot.2007.303","article-title":"Determination of drug permeability and prediction of drug absorption in Caco-2 monolayers","volume":"2","author":"Hubatsch","year":"2007","journal-title":"Nat. Protoc."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1389","DOI":"10.1111\/j.1476-5381.1996.tb15550.x","article-title":"Transport and epithelial secretion of the cardiac glycoside, digoxin, by human intestinal epithelial (Caco-2) cells","volume":"118","author":"Cavet","year":"1996","journal-title":"Br. J. Pharmacol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1093\/jac\/dkq501","article-title":"Potential of novel antiretrovirals to modulate expression and function of drug transporters in vitro","volume":"66","author":"Zembruski","year":"2011","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1893","DOI":"10.1124\/dmd.106.011148","article-title":"Innovative methods to study human intestinal drug metabolism in vitro: Precision-cut slices compared with ussing chamber preparations","volume":"34","author":"Ungell","year":"2006","journal-title":"Drug Metab. Dispos."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1002\/pro.2387","article-title":"Refined structures of mouse P-glycoprotein","volume":"23","author":"Li","year":"2014","journal-title":"Protein Sci."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/15\/2\/242\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:22:13Z","timestamp":1760134933000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/15\/2\/242"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,2,18]]},"references-count":84,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2022,2]]}},"alternative-id":["ph15020242"],"URL":"https:\/\/doi.org\/10.3390\/ph15020242","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,2,18]]}}}