P-glycoprotein (ABCB1), an ATP-binding cassette efflux transporter, limits intestinal absorption of its substrates and is a common site of drug-drug interactions. Drug-mediated induction of intestinal ABCB1 is a clinically relevant phenomenon associated with significantly decreased drug bioavailability. Currently, there are no well-established human models for evaluating its induction, so drug regulatory authorities provide no recommendations for in vitro/ex vivo testing drugs' ABCB1-inducing activity. Human precision-cut intestinal slices (hPCISs) contain cells in their natural environment and express physiological levels of nuclear factors required for ABCB1 induction. We found that hPCISs incubated in William's Medium E for 48 h maintained intact morphology, ATP content, and ABCB1 efflux activity. Here, we asked whether rifampicin (a model ligand of pregnane X receptor, PXR), at 30 μM, induces functional expression of ABCB1 in hPCISs over 24- and 48-h incubation (the time to allow complete induction to occur). Rifampicin significantly increased gene expression, protein levels, and efflux activity of ABCB1. Moreover, we described dynamic changes in ABCB1 transcript levels in hPCISs over 48 h incubation. We also observed that peaks of induction are achieved among donors at different times, and the extent of ABCB1 gene induction is proportional to PXR mRNA levels in the intestine. In conclusion, we showed that hPCISs incubated in conditions comparable to those used for inhibition studies can be used to evaluate drugs' ABCB1-inducing potency in the human intestine. Thus, hPCISs may be valuable experimental tools that can be prospectively used in complex experimental evaluation of drug-drug interactions.

Department of Hepato Pancreato Biliary Surgery and Liver Transplantation University Medical Center Groningen University of Groningen Groningen Netherlands

Department of Medical Biochemistry Faculty of Medicine in Hradec Kralove Charles University Hradec Kralove Czechia

Department of Pharmaceutical Technology and Biopharmacy Faculty of Science and Engineering Groningen Research Institute of Pharmacy Groningen Netherlands

Department of Pharmacology and Toxicology Faculty of Pharmacy in Hradec Kralove Charles University Hradec Kralove Czechia

Department of Surgery University Hospital Hradec Kralove Hradec Kralove Czechia

Graduate School of Science Faculty of Science and Engineering University of Groningen Groningen Netherlands

Zobrazit více v PubMed

Albermann N., Schmitz-Winnenthal F. H., Z’graggen K., Volk C., Hoffmann M. M., Haefeli W. E., et al. (2005). Expression of the Drug Transporters MDR1/ABCB1, MRP1/ABCC1, MRP2/ABCC2, BCRP/ABCG2, and PXR in Peripheral Blood Mononuclear Cells and Their Relationship with the Expression in Intestine and Liver. Biochem. Pharmacol. 70, 949–958. 10.1016/j.bcp.2005.06.018 PubMed DOI

Begley R., Das M., Zhong L., Ling J., Kearney B. P., Custodio J. M. (2018). Pharmacokinetics of Tenofovir Alafenamide when Coadministered with Other HIV Antiretrovirals. J. Acquir Immune Defic Syndr. 78, 465–472. 10.1097/qai.0000000000001699 PubMed DOI

Burger H., Van Tol H., Brok M., Wiemer E. A. C., De Bruijn E. A., Guetens G., et al. (2005). Chronic Imatinib Mesylate Exposure Leads to Reduced Intracellular Drug Accumulation by Induction of the ABCG2 (BCRP) and ABCB1 (MDR1) Drug Transport Pumps. Cancer Biol. Ther. 4, 747–752. 10.4161/cbt.4.7.1826 PubMed DOI

Cerveny L., Svecova L., Anzenbacherova E., Vrzal R., Staud F., Dvorak Z., et al. (2007). Valproic Acid Induces CYP3A4 and MDR1 Gene Expression by Activation of Constitutive Androstane Receptor and Pregnane X Receptor Pathways. Drug Metab. Dispos 35, 1032–1041. 10.1124/dmd.106.014456 PubMed DOI

Cole S., Kerwash E., Andersson A. (2020). A Summary of the Current Drug Interaction Guidance from the European Medicines Agency and Considerations of Future Updates. Drug Metab. Pharmacokinet. 35, 2–11. 10.1016/j.dmpk.2019.11.005 PubMed DOI

De Graaf I. A. M., Olinga P., De Jager M. H., Merema M. T., De Kanter R., Van De Kerkhof E. G., et al. (2010). Preparation and Incubation of Precision-Cut Liver and Intestinal Slices for Application in Drug Metabolism and Toxicity Studies. Nat. Protoc. 5, 1540–1551. 10.1038/nprot.2010.111 PubMed DOI

Dhhs (2019). Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV. Department of Health and Human Services. Available at: https://clinicalinfo.hiv.gov/sites/default/files/guidelines/documents/AdultandAdolescentGL.pdf (Accessed September24, 2020).

Elmeliegy M., Vourvahis M., Guo C., Wang D. D. (2020). Effect of P-Glycoprotein (P-Gp) Inducers on Exposure of P-Gp Substrates: Review of Clinical Drug-Drug Interaction Studies. Clin. Pharmacokinet. 59, 699–714. 10.1007/s40262-020-00867-1 PubMed DOI PMC

Evans-Jones J. G., Cottle L. E., Back D. J., Gibbons S., Beeching N. J., Carey P. B., et al. (2010). Recognition of Risk for Clinically Significant Drug Interactions Among HIV-Infected Patients Receiving Antiretroviral Therapy. Clin. Infect. Dis. 50, 1419–1421. 10.1086/652149 PubMed DOI

FDA (2020). U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research. Vitro Drug Interaction Studies — Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions Guidance for Industry. Avabilable at: https://www.fda.gov/media/134582/download.(accessed September23rd, 2020).

Fenner K., Troutman M., Kempshall S., Cook J., Ware J., Smith D., et al. (2009). Drug-drug Interactions Mediated through P-Glycoprotein: Clinical Relevance and In Vitro-In Vivo Correlation Using Digoxin as a Probe Drug. Clin. Pharmacol. Ther. 85, 173–181. 10.1038/clpt.2008.195 PubMed DOI

Forster S., Thumser A. E., Hood S. R., Plant N. (2012). Characterization of Rhodamine-123 as a Tracer Dye for Use in In Vitro Drug Transport Assays. PLoS One 7, e33253. 10.1371/journal.pone.0033253 PubMed DOI PMC

Fritz A., Busch D., Lapczuk J., Ostrowski M., Drozdzik M., Oswald S. (2019). Expression of Clinically Relevant Drug‐metabolizing Enzymes along the Human Intestine and Their Correlation to Drug Transporters and Nuclear Receptors: An Intra‐subject Analysis. Basic Clin. Pharmacol. Toxicol. 124, 245–255. 10.1111/bcpt.13137 PubMed DOI

Giacomini K. M., Galetin A., Huang S. M. (2018). The International Transporter Consortium: Summarizing Advances in the Role of Transporters in Drug Development. Clin. Pharmacol. Ther. 104, 766–771. 10.1002/cpt.1224 PubMed DOI

International Transporter Consortium Giacomini K. M., Giacomini K. M., Huang S. M., Tweedie D. J., Benet L. Z., Brouwer K. L., et al. (2010). Membrane Transporters in Drug Development. Nat. Rev. Drug Discov. 9, 215–236. 10.1038/nrd3028 PubMed DOI PMC

Giacomini K. M., Huang S.-M. (2013). Transporters in Drug Development and Clinical Pharmacology. Clin. Pharmacol. Ther. 94, 3–9. 10.1038/clpt.2013.86 PubMed DOI

Goto M., Masuda S., Saito H., Inui K.-i. (2003). Decreased Expression of P-Glycoprotein during Differentiation in the Human Intestinal Cell Line Caco-2. Biochem. Pharmacol. 66, 163–170. 10.1016/s0006-2952(03)00242-9 PubMed DOI

Greiner B., Eichelbaum M., Fritz P., Kreichgauer H.-P., Von Richter O., Zundler J., et al. (1999). The Role of Intestinal P-Glycoprotein in the Interaction of Digoxin and Rifampin. J. Clin. Invest. 104, 147–153. 10.1172/jci6663 PubMed DOI PMC

Groothuis G. M., De Graaf I. A. (2013). Precision-cut Intestinal Slices as In Vitro Tool for Studies on Drug Metabolism. Curr. Drug Metab. 14, 112–119. PubMed

Guo Y., Chu X., Parrott N. J., Brouwer K. L. R., Hsu V., Nagar S., et al. International Transporter Consortium. (2018). Advancing Predictions of Tissue and Intracellular Drug Concentrations Using In Vitro , Imaging and Physiologically Based Pharmacokinetic Modeling Approaches. Clin. Pharmacol. Ther. 104, 865–889. 10.1002/cpt.1183 PubMed DOI PMC

Han T., Everett R. S., Proctor W. R., Ng C. M., Costales C. L., Brouwer K. L. R., et al. (2013). Organic Cation Transporter 1 (OCT1/mOct1) Is Localized in the Apical Membrane of Caco-2 Cell Monolayers and Enterocytes. Mol. Pharmacol. 84, 182–189. 10.1124/mol.112.084517 PubMed DOI PMC

Harwood M. D., Achour B., Neuhoff S., Russell M. R., Carlson G., Warhurst G., et al. (2016). In Vitro-In Vivo Extrapolation Scaling Factors for Intestinal P-Glycoprotein and Breast Cancer Resistance Protein: Part I: A Cross-Laboratory Comparison of Transporter-Protein Abundances and Relative Expression Factors in Human Intestine and Caco-2 Cells. Drug Metab. Disposition 44, 297–307. 10.1124/dmd.115.067371 PubMed DOI

Honjo Y., Hrycyna C. A., Yan Q. W., Medina-Pérez W. Y., Robey R. W., Van De Laar A., et al. (2001). Acquired Mutations in the MXR/BCRP/ABCP Gene Alter Substrate Specificity in MXR/BCRP/ABCP-overexpressing Cells. Cancer Res. 61, 6635–6639. PubMed

Hyrsova L., Smutny T., Carazo A., Moravcik S., Mandikova J., Trejtnar F., et al. (2016). The Pregnane X Receptor Down-Regulates Organic Cation Transporter 1 (SLC22A1) in Human Hepatocytes by Competing for ("squelching") SRC-1 Coactivator. Br. J. Pharmacol. 173, 1703–1715. 10.1111/bph.13472 PubMed DOI PMC

Jouan E., Le Vee M., Denizot C., Da Violante G., Fardel O. (2014). The Mitochondrial Fluorescent Dye Rhodamine 123 Is a High-Affinity Substrate for Organic Cation Transporters (OCTs) 1 and 2. Fundam. Clin. Pharmacol. 28, 65–77. 10.1111/j.1472-8206.2012.01071.x PubMed DOI

Kalgutkar A. S., Frederick K. S., Chupka J., Feng B., Kempshall S., Mireles R. J., et al. (2009). N-(3,4-dimethoxyphenethyl)-4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2[1H]-yl)-6,7-dimethoxyquinazolin-2-amine (CP-100,356) as a "chemical Knock-Out Equivalent" to Assess the Impact of Efflux Transporters on Oral Drug Absorption in the Rat. J. Pharm. Sci. 98, 4914–4927. 10.1002/jps.21756 PubMed DOI

Kalliokoski A., Niemi M. (2009). Impact of OATP Transporters on Pharmacokinetics. Br. J. Pharmacol. 158, 693–705. 10.1111/j.1476-5381.2009.00430.x PubMed DOI PMC

Katayama K., Fujiwara C., Noguchi K., Sugimoto Y. (2016). RSK1 Protects P-glycoprotein/ABCB1 against Ubiquitin-Proteasomal Degradation by Downregulating the Ubiquitin-Conjugating Enzyme E2 R1. Sci. Rep. 6, 36134. 10.1038/srep36134 PubMed DOI PMC

Kong Q., Han Z., Zuo X., Wei H., Huang W. (2016). Co-expression of Pregnane X Receptor and ATP-Binding Cassette Sub-family B Member 1 in Peripheral Blood: A Prospective Indicator for Drug Resistance Prediction in Non-small Cell Lung Cancer. Oncol. Lett. 11, 3033–3039. 10.3892/ol.2016.4369 PubMed DOI PMC

Kumar P., Gordon L. A., Brooks K. M., George J. M., Kellogg A., Mcmanus M., et al. (2017). Differential Influence of the Antiretroviral Pharmacokinetic Enhancers Ritonavir and Cobicistat on Intestinal P-Glycoprotein Transport and the Pharmacokinetic/Pharmacodynamic Disposition of Dabigatran. Antimicrob. Agents Chemother. 61. 10.1128/aac.01201-17 PubMed DOI PMC

Lamba J. K., Lin Y. S., Schuetz E. G., Thummel K. E. (2002). Genetic Contribution to Variable Human CYP3A-Mediated Metabolism. Adv. Drug Deliv. Rev. 54, 1271–1294. 10.1016/s0169-409x(02)00066-2 PubMed DOI

Li M., De Graaf I. A. M., De Jager M. H., Groothuis G. M. M. (2017a). P-gp Activity and Inhibition in the Different Regions of Human Intestineex Vivo. Biopharm. Drug Dispos. 38, 127–138. 10.1002/bdd.2047 PubMed DOI

Li M., De Graaf I. A. M., De Jager M. H., Groothuis G. M. M. (2015). Rat Precision-Cut Intestinal Slices to Study P-Gp Activity and the Potency of its Inhibitors Ex Vivo . Toxicol. Vitro 29, 1070–1078. 10.1016/j.tiv.2015.04.011 PubMed DOI

Li M., De Graaf I. A. M., Van De Steeg E., De Jager M. H., Groothuis G. M. M. (2017b). The Consequence of Regional Gradients of P-Gp and CYP3A4 for Drug-Drug Interactions by P-Gp Inhibitors and the P-gp/CYP3A4 Interplay in the Human Intestine Ex Vivo . Toxicol. Vitro 40, 26–33. 10.1016/j.tiv.2016.12.002 PubMed DOI

Lindell M., Karlsson M. O., Lennernäs H., Påhlman L., Lang M. A. (2003). Variable Expression of CYP and Pgp Genes in the Human Small Intestine. Eur. J. Clin. Invest. 33, 493–499. 10.1046/j.1365-2362.2003.01154.x PubMed DOI

Luedtke D., Marzin K., Jungnik A., Von Wangenheim U., Dallinger C. (2018). Effects of Ketoconazole and Rifampicin on the Pharmacokinetics of Nintedanib in Healthy Subjects. Eur. J. Drug Metab. Pharmacokinet. 43, 533–541. 10.1007/s13318-018-0467-9 PubMed DOI PMC

Lutz J. D., Kirby B. J., Wang L., Song Q., Ling J., Massetto B., et al. (2018). Cytochrome P450 3A Induction Predicts P-Glycoprotein Induction; Part 1: Establishing Induction Relationships Using Ascending Dose Rifampin. Clin. Pharmacol. Ther. 104, 1182–1190. 10.1002/cpt.1073 PubMed DOI PMC

Marchetti S., Mazzanti R., Beijnen J. H., Schellens J. H. M. (2007). Concise Review: Clinical Relevance of Drug-Drug and Herb-Drug Interactions Mediated by the ABC Transporter ABCB1 (MDR1, P‐glycoprotein). Oncol. 12, 927–941. 10.1634/theoncologist.12-8-927 PubMed DOI

Martin P., Gillen M., Millson D., Oliver S., Brealey C., Elsby R., et al. (2015). Effects of Fostamatinib on the Pharmacokinetics of Digoxin (A P-Glycoprotein Substrate): Results from In Vitro and Phase I Clinical Studies. Clin. Ther. 37, 2811–2822. 10.1016/j.clinthera.2015.09.018 PubMed DOI

Martinec O., Huliciak M., Staud F., Cecka F., Vokral I., Cerveny L. (2019). 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. Antimicrob. Agents Chemother. 63. 10.1128/aac.00910-19 PubMed DOI PMC

Murakami T. (2017). Absorption Sites of Orally Administered Drugs in the Small Intestine. Expert Opin. Drug Discov. 12, 1219–1232. 10.1080/17460441.2017.1378176 PubMed DOI

Negoro R., Takayama K., Nagamoto Y., Sakurai F., Tachibana M., Mizuguchi H. (2016). Modeling of Drug-Mediated CYP3A4 Induction by Using Human iPS Cell-Derived Enterocyte-like Cells. Biochem. Biophysical Res. Commun. 472, 631–636. 10.1016/j.bbrc.2016.03.012 PubMed DOI

Oostendorp R. L., Beijnen J. H., Schellens J. H. M. (2009). The Biological and Clinical Role of Drug Transporters at the Intestinal Barrier. Cancer Treat. Rev. 35, 137–147. 10.1016/j.ctrv.2008.09.004 PubMed DOI

Oswald S. (2019). Organic Anion Transporting Polypeptide (OATP) Transporter Expression, Localization and Function in the Human Intestine. Pharmacol. Ther. 195, 39–53. 10.1016/j.pharmthera.2018.10.007 PubMed DOI

Owen A., Chandler B., Back D. J., Khoo S. H. (2004). Expression of Pregnane-X-Receptor Transcript in Peripheral Blood Mononuclear Cells and Correlation with MDR1 mRNA. Antivir. Ther. 9, 819–821. PubMed

Pokharel D., Roseblade A., Oenarto V., Lu J. F., Bebawy M. (2017). Proteins Regulating the Intercellular Transfer and Function of P-Glycoprotein in Multidrug-Resistant Cancer. Ecancermedicalscience 11, 768. 10.3332/ecancer.2017.768 PubMed DOI PMC

Rodrigues A. C., Curi R., Genvigir F. D. V., Hirata M. H., Hirata R. D. C. (2009). The Expression of Efflux and Uptake Transporters Are Regulated by Statins in Caco-2 and HepG2 Cells. Acta Pharmacol. Sin 30, 956–964. 10.1038/aps.2009.85 PubMed DOI PMC

Ruigrok M. J. R., Tomar J., Frijlink H. W., Melgert B. N., Hinrichs W. L. J., Olinga P. (2019). The Effects of Oxygen Concentration on Cell Death, Anti-oxidant Transcription, Acute Inflammation, and Cell Proliferation in Precision-Cut Lung Slices. Sci. Rep. 9, 16239. 10.1038/s41598-019-52813-2 PubMed DOI PMC

Sandson N. (2005). Economic Grand Rounds: Drug-Drug Interactions: The Silent Epidemic. Ps 56, 22–24. 10.1176/appi.ps.56.1.22 PubMed DOI

Seden K., Back D., Khoo S. (2009). Antiretroviral Drug Interactions: Often Unrecognized, Frequently Unavoidable, Sometimes Unmanageable. J. Antimicrob. Chemother. 64, 5–8. 10.1093/jac/dkp152 PubMed DOI

Shirasaka Y., Kawasaki M., Sakane T., Omatsu H., Moriya Y., Nakamura T., et al. (2006). Induction of Human P-Glycoprotein in Caco-2 Cells: Development of a Highly Sensitive Assay System for P-Glycoprotein-Mediated Drug Transport. Drug Metab. Pharmacokinet. 21, 414–423. 10.2133/dmpk.21.414 PubMed DOI

Siegmund W., Ludwig K., Engel G., Zschiesche M., Franke G., Hoffmann A., et al. (2003). Variability of Intestinal Expression of P-Glycoprotein in Healthy Volunteers as Described by Absorption of Talinolol from Four Bioequivalent Tablets. J. Pharm. Sci. 92, 604–610. 10.1002/jps.10327 PubMed DOI

Smutny T., Mani S., Pavek P. (2013). Post-translational and post-transcriptional Modifications of Pregnane X Receptor (PXR) in Regulation of the Cytochrome P450 Superfamily. Cdm 14, 1059–1069. 10.2174/1389200214666131211153307 PubMed DOI PMC

Storch C. H., Theile D., Lindenmaier H., Haefeli W. E., Weiss J. (2007). Comparison of the Inhibitory Activity of Anti-HIV Drugs on P-Glycoprotein. Biochem. Pharmacol. 73, 1573–1581. 10.1016/j.bcp.2007.01.027 PubMed DOI

Su S. F., Huang J. D. (1996). Inhibition of the Intestinal Digoxin Absorption and Exsorption by Quinidine. Drug Metab. Dispos 24, 142–147. PubMed

Sun H., Chow E. C., Liu S., Du Y., Pang K. S. (2008). The Caco-2 Cell Monolayer: Usefulness and Limitations. Expert Opin. Drug Metab. Toxicol. 4, 395–411. 10.1517/17425255.4.4.395 PubMed DOI

Tjernberg A., Markova N., Griffiths W. J., Hallén D. (2006). DMSO-related Effects in Protein Characterization. J. Biomol. Screen. 11, 131–137. 10.1177/1087057105284218 PubMed DOI

Van De Kerkhof E. G., De Graaf I. A. M., Ungell A.-L. B., Groothuis G. M. M. (2008). Induction of Metabolism and Transport in Human Intestine: Validation of Precision-Cut Slices as a Tool to Study Induction of Drug Metabolism in Human Intestine In Vitro . Drug Metab. Dispos 36, 604–613. 10.1124/dmd.107.018820 PubMed DOI

Van Roon E. N., Flikweert S., Le Comte M., Langendijk P. N. J., Kwee-Zuiderwijk W. J. M., Smits P., et al. (2005). Clinical Relevance of Drug-Drug Interactions. Drug Saf. 28, 1131–1139. 10.2165/00002018-200528120-00007 PubMed DOI

Varma M. V. S., Sateesh K., Panchagnula R. (2005). Functional Role of P-Glycoprotein in Limiting Intestinal Absorption of Drugs: Contribution of Passive Permeability to P-Glycoprotein Mediated Efflux Transport. Mol. Pharmaceutics 2, 12–21. 10.1021/mp0499196 PubMed DOI

Wang H., Lecluyse E. L. (2003). Role of Orphan Nuclear Receptors in the Regulation of Drug-Metabolising Enzymes. Clin. Pharmacokinet. 42, 1331–1357. 10.2165/00003088-200342150-00003 PubMed DOI

Wang Q., Herrera-Ruiz D., Mathis A. S., Cook T. J., Bhardwaj R. K., Knipp G. T. (2005). Expression of PPAR, RXR Isoforms and Fatty Acid Transporting Proteins in the Rat and Human Gastrointestinal Tracts. J. Pharm. Sci. 94, 363–372. 10.1002/jps.20264 PubMed DOI

Wei Z., Chen M., Zhang Y., Wang X., Jiang S., Wang Y., et al. (2013). No Correlation of Hsa-miR-148a with Expression of PXR or CYP3A4 in Human Livers from Chinese Han Population. PLoS One 8, e59141. 10.1371/journal.pone.0059141 PubMed DOI PMC

Weiss J., Herzog M., König S., Storch C. H., Ketabi-Kiyanvash N., Haefeli W. E. (2009). Induction of Multiple Drug Transporters by Efavirenz. J. Pharmacol. Sci. 109, 242–250. 10.1254/jphs.08209fp PubMed DOI

Westphal K., Weinbrenner A., Zschiesche M., Franke G., Knoke M., Oertel R., et al. (2000). Induction of P-Glycoprotein by Rifampin Increases Intestinal Secretion of Talinolol in Human Beings: a New Type of Drug/drug Interaction. Clin. Pharmacol. Ther. 68, 345–355. 10.1067/mcp.2000.109797 PubMed DOI

Wu J., Lin N., Li F., Zhang G., He S., Zhu Y., et al. (2016). Induction of P-Glycoprotein Expression and Activity by Aconitum Alkaloids: Implication for Clinical Drug-Drug Interactions. Sci. Rep. 6, 25343. 10.1038/srep25343 PubMed DOI PMC

Yamazaki S., Costales C., Lazzaro S., Eatemadpour S., Kimoto E., Varma M. V. (2019). Physiologically‐Based Pharmacokinetic Modeling Approach to Predict Rifampin‐Mediated Intestinal P‐Glycoprotein Induction. CPT Pharmacometrics Syst. Pharmacol. 8, 634–642. 10.1002/psp4.12458 PubMed DOI PMC

Yamazaki S., Loi C.-M., Kimoto E., Costales C., Varma M. V. (2018). Application of Physiologically Based Pharmacokinetic Modeling in Understanding Bosutinib Drug-Drug Interactions: Importance of Intestinal P-Glycoprotein. Drug Metab. Dispos 46, 1200–1211. 10.1124/dmd.118.080424 PubMed DOI

Zamek-Gliszczynski M. J., Patel M., Yang X., Lutz J. D., Chu X., Brouwer K. L. R., et al. (2021). Intestinal P-gp and Putative Hepatic OATP1B Induction: International Transporter Consortium Perspective on Drug Development Implications. Clin. Pharmacol. Ther. 109, 55–64. 10.1002/cpt.1916 PubMed DOI PMC

Effect of P-glycoprotein and Cotreatment with Sofosbuvir on the Intestinal Permeation of Tenofovir Disoproxil Fumarate and Tenofovir Alafenamide Fumarate

Extending the viability of human precision-cut intestinal slice model for drug metabolism studies

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