{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T00:42:41Z","timestamp":1790037761348,"version":"4.0.1"},"reference-count":51,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2020,5,27]],"date-time":"2020-05-27T00:00:00Z","timestamp":1590537600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001665","name":"Agence Nationale de la Recherche","doi-asserted-by":"publisher","award":["ANR-11-INBS-0006."],"award-info":[{"award-number":["ANR-11-INBS-0006."]}],"id":[{"id":"10.13039\/501100001665","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>The multidrug resistance-associated protein 2 (MRP2) mediates the biliary excretion of drugs and metabolites. [99mTc]mebrofenin may be employed as a probe for hepatic MRP2 activity because its biliary excretion is predominantly mediated by this transporter. As the liver uptake of [99mTc]mebrofenin depends on organic anion-transporting polypeptide (OATP) activity, a safe protocol for targeted inhibition of hepatic MRP2 is needed to study the intrinsic role of each transporter system. Diltiazem (DTZ) and cyclosporin A (CsA) were first confirmed to be potent MRP2 inhibitors in vitro. Dynamic acquisitions were performed in rats (n = 5\u20136 per group) to assess the kinetics of [99mTc]mebrofenin in the liver, intestine and heart-blood pool after increasing doses of inhibitors. Their impact on hepatic blood flow was assessed using Doppler ultrasound (n = 4). DTZ (s.c., 10 mg\/kg) and low-dose CsA (i.v., 0.01 mg\/kg) selectively decreased the transfer of [99mTc]mebrofenin from the liver to the bile (k3). Higher doses of DTZ and CsA did not further decrease k3 but dose-dependently decreased the uptake (k1) and backflux (k2) rate constants between blood and liver. High dose of DTZ (i.v., 3 mg\/kg) but not CsA (i.v., 5 mg\/kg) significantly decreased the blood flow in the portal vein and hepatic artery. Targeted pharmacological inhibition of hepatic MRP2 activity can be achieved in vivo without impacting OATP activity and liver blood flow. Clinical studies are warranted to validate [99mTc]mebrofenin in combination with low-dose CsA as a novel substrate\/inhibitor pair to untangle the role of OATP and MRP2 activity in liver diseases.<\/jats:p>","DOI":"10.3390\/pharmaceutics12060486","type":"journal-article","created":{"date-parts":[[2020,5,29]],"date-time":"2020-05-29T00:44:02Z","timestamp":1590713042000},"page":"486","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Validation of Pharmacological Protocols for Targeted Inhibition of Canalicular MRP2 Activity in Hepatocytes Using [99mTc]mebrofenin Imaging in Rats"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5247-4871","authenticated-orcid":false,"given":"Sol\u00e8ne","family":"Marie","sequence":"first","affiliation":[{"name":"Universit\u00e9 Paris-Saclay, CEA, Inserm, CNRS, BioMaps, Service Hospitalier Fr\u00e9d\u00e9ric Joliot, 4 place du G\u00e9n\u00e9ral Leclerc, 91401 Orsay, France"},{"name":"D\u00e9partement de Pharmacie Clinique, Facult\u00e9 de Pharmacie, Universit\u00e9 Paris-Saclay, 92296 Ch\u00e2tenay-Malabry, France"},{"name":"AP-HP, Universit\u00e9 Paris-Saclay, H\u00f4pital Bic\u00eatre, Pharmacie Clinique, 94270 Le Kremlin Bic\u00eatre, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3700-7690","authenticated-orcid":false,"given":"Irene","family":"Hern\u00e1ndez-Lozano","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louise","family":"Breuil","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris-Saclay, CEA, Inserm, CNRS, BioMaps, Service Hospitalier Fr\u00e9d\u00e9ric Joliot, 4 place du G\u00e9n\u00e9ral Leclerc, 91401 Orsay, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wadad","family":"Saba","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris-Saclay, CEA, Inserm, CNRS, BioMaps, Service Hospitalier Fr\u00e9d\u00e9ric Joliot, 4 place du G\u00e9n\u00e9ral Leclerc, 91401 Orsay, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony","family":"Novell","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris-Saclay, CEA, Inserm, CNRS, BioMaps, Service Hospitalier Fr\u00e9d\u00e9ric Joliot, 4 place du G\u00e9n\u00e9ral Leclerc, 91401 Orsay, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Luc","family":"Gennisson","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris-Saclay, CEA, Inserm, CNRS, BioMaps, Service Hospitalier Fr\u00e9d\u00e9ric Joliot, 4 place du G\u00e9n\u00e9ral Leclerc, 91401 Orsay, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oliver","family":"Langer","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology, Medical University of Vienna, 1090 Vienna, Austria"},{"name":"Preclinical Molecular Imaging, AIT Austrian Institute of Technology GmbH, 2444 Seibersdorf, Austria"},{"name":"Division of Nuclear Medicine, Department of Biomedical Imaging und Image-guided Therapy, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles","family":"Truillet","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris-Saclay, CEA, Inserm, CNRS, BioMaps, Service Hospitalier Fr\u00e9d\u00e9ric Joliot, 4 place du G\u00e9n\u00e9ral Leclerc, 91401 Orsay, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0755-2030","authenticated-orcid":false,"given":"Nicolas","family":"Tournier","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris-Saclay, CEA, Inserm, CNRS, BioMaps, Service Hospitalier Fr\u00e9d\u00e9ric Joliot, 4 place du G\u00e9n\u00e9ral Leclerc, 91401 Orsay, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,5,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"S23","DOI":"10.1002\/jcph.671","article-title":"Importance of hepatic transporters in clinical disposition of drugs and their metabolites","volume":"56","author":"Patel","year":"2016","journal-title":"J. Clin. Pharmacol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Marin, J. (2012). Plasma membrane transporters in modern liver pharmacology. Scientifica, 2012.","DOI":"10.6064\/2012\/428139"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1002\/cpt.1224","article-title":"The international transporter consortium: Summarizing advances in the role of transporters in drug development","volume":"104","author":"Giacomini","year":"2018","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"900","DOI":"10.1002\/cpt.1115","article-title":"Disease-associated changes in drug transporters may impact the pharmacokinetics and\/or toxicity of drugs: A white paper from the international transporter consortium","volume":"104","author":"Evers","year":"2018","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1111\/j.1476-5381.2009.00430.x","article-title":"Impact of OATP transporters on pharmacokinetics","volume":"158","author":"Kalliokoski","year":"2009","journal-title":"Br. J. Pharmacol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"890","DOI":"10.1002\/cpt.1112","article-title":"Transporters in drug development: 2018 ITC recommendations for transporters of emerging clinical importance","volume":"104","author":"Taub","year":"2018","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_7","first-page":"1146","article-title":"Both cMOAT\/MRP2 and another unknown transporter(s) are responsible for the biliary excretion of glucuronide conjugate of the nonpeptide angiotensin II antagonist, telmisaltan","volume":"28","author":"Nishino","year":"2000","journal-title":"Drug Metab. Dispos."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1816","DOI":"10.1007\/s11095-009-9896-0","article-title":"Identification of novel specific and general inhibitors of the three major human ATP-binding cassette transporters P-gp, BCRP and MRP2 among registered drugs","volume":"26","author":"Matsson","year":"2009","journal-title":"Pharm. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"778","DOI":"10.1002\/hep.21359","article-title":"Hepatobiliary transporters and drug-induced cholestasis","volume":"44","author":"Meier","year":"2006","journal-title":"Hepatology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2282","DOI":"10.1016\/j.xphs.2017.04.053","article-title":"Effect of Liver disease on hepatic transporter expression and function","volume":"106","author":"Thakkar","year":"2017","journal-title":"J. Pharm. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"135","DOI":"10.3390\/ijms16010135","article-title":"Quantification of drug transport function across the multiple resistance-associated protein 2 (Mrp2) in rat livers","volume":"16","author":"Bonnaventure","year":"2015","journal-title":"Int. J. Mol. Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1021\/mp060011k","article-title":"Methods to evaluate biliary excretion of drugs in humans: An updated review","volume":"3","author":"Ghibellini","year":"2006","journal-title":"Mol. Pharm."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1080\/17425255.2020.1718107","article-title":"Use of imaging to assess the activity of hepatic transporters","volume":"16","author":"Langer","year":"2020","journal-title":"Expert Opin. Drug Metab. Toxicol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1016\/j.pharmthera.2018.04.006","article-title":"Imaging techniques to study drug transporter function in vivo","volume":"189","author":"Tournier","year":"2018","journal-title":"Pharmacol. Ther."},{"key":"ref_15","first-page":"633","article-title":"Development of new radiopharmaceuticals based on n-substitution of iminodiacetic acid","volume":"17","author":"Loberg","year":"1976","journal-title":"J. Nucl. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1002\/hep.1840090123","article-title":"Technetium-99m-iminodiacetic acid organic anions: Review of biokinetics and clinical application in hepatology","volume":"9","author":"Krishnamurthy","year":"1989","journal-title":"Hepatology"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1851","DOI":"10.1007\/s11095-008-9597-0","article-title":"Use of Tc-99m mebrofenin as a clinical probe to assess altered hepatobiliary transport: Integration of in vitro, pharmacokinetic modeling, and simulation studies","volume":"25","author":"Ghibellini","year":"2008","journal-title":"Pharm. Res."},{"key":"ref_18","first-page":"997","article-title":"Technetium-99m-Labeled N-(2,6-Dimethylphenylcarbamoylmethyl) Iminodiacetic Acid (Tc-99m HIDA): A new radiopharmaceutical for hepatobiliary imaging studies","volume":"18","author":"Ryan","year":"1977","journal-title":"J. Nucl. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2335","DOI":"10.1016\/j.xphs.2017.04.031","article-title":"Imaging probes and modalities for the study of solute carrier O (SLCO)-transport function in vivo","volume":"106","author":"Marie","year":"2017","journal-title":"J. Pharm. Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"738","DOI":"10.1016\/j.jhep.2010.07.047","article-title":"Transporters involved in the hepatic uptake of 99mTc-mebrofenin and indocyanine green","volume":"54","author":"Heger","year":"2011","journal-title":"J. Hepatol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1140","DOI":"10.2967\/jnumed.109.062448","article-title":"Adenosine triphosphate\u2013binding cassette subfamily c member 2 is the major transporter of the hepatobiliary imaging agent 99mTc-mebrofenin","volume":"50","author":"Bhargava","year":"2009","journal-title":"J. Nucl. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1007\/s00280-004-0793-2","article-title":"In vivo imaging of hepatobiliary transport function mediated by multidrug resistance associated protein and P-glycoprotein","volume":"54","author":"Hendrikse","year":"2004","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1007\/s002590050390","article-title":"Visualization of multidrug resistance in vivo","volume":"26","author":"Hendrikse","year":"1999","journal-title":"Eur. J. Nucl. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"742","DOI":"10.2967\/jnumed.109.069435","article-title":"Nuclear imaging techniques for the assessment of hepatic function in liver surgery and transplantation","volume":"51","author":"Bennink","year":"2010","journal-title":"J. Nucl. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1038\/clpt.2009.138","article-title":"Imaging the function of P-Glycoprotein with radiotracers: Pharmacokinetics and in vivo applications","volume":"86","author":"Kannan","year":"2009","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1007\/s00259-011-1941-7","article-title":"A comparative small-animal PET evaluation of [11C]tariquidar, [11C]elacridar and (R)-[11C]verapamil for detection of P-glycoprotein-expressing murine breast cancer","volume":"39","author":"Wanek","year":"2012","journal-title":"Eur. J. Nucl. Med. Mol. Imaging"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1124\/dmd.118.080408","article-title":"A clinical quantitative evaluation of hepatobiliary transport of [11C]Dehydropravastatin in humans using positron emission tomography","volume":"46","author":"Kaneko","year":"2018","journal-title":"Drug Metab. Dispos."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"4740","DOI":"10.1021\/jm300212s","article-title":"Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): Influence of protein expression on drug\u2013drug interactions","volume":"55","author":"Karlgren","year":"2012","journal-title":"J. Med. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1016\/j.tube.2015.08.004","article-title":"Inhibitory potential of tuberculosis drugs on ATP-binding cassette drug transporters","volume":"96","author":"Russel","year":"2016","journal-title":"Tuberculosis"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"624","DOI":"10.2967\/jnumed.112.108233","article-title":"In vivo visualization and quantification of (disturbed) oatp-mediated hepatic uptake and mrp2-mediated biliary excretion of 99mTc-mebrofenin in mice","volume":"54","author":"Neyt","year":"2013","journal-title":"J. Nucl. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1124\/dmd.113.054304","article-title":"Risk Factors for development of cholestatic drug-induced liver injury: Inhibition of hepatic basolateral bile acid transporters multidrug resistance-associated proteins 3 and 4","volume":"42","author":"Ferslew","year":"2014","journal-title":"Drug Metab. Dispos."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1637","DOI":"10.1007\/s11095-017-2160-0","article-title":"In vitro transport activity and trafficking of MRP2\/ABCC2 Polymorphic variants","volume":"34","author":"Wen","year":"2017","journal-title":"Pharm. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1186\/s13550-018-0434-0","article-title":"Impact of rifampicin-inhibitable transport on the liver distribution and tissue kinetics of erlotinib assessed with PET imaging in rats","volume":"8","author":"Amor","year":"2018","journal-title":"EJNMMI Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1002\/bdd.568","article-title":"Pharmacokinetics and metabolism of diltiazem in rats: Comparing single vs. repeated subcutaneous injections in vivo","volume":"28","author":"Yeung","year":"2007","journal-title":"Biopharm. Drug Dispos."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"741","DOI":"10.2967\/jnumed.111.098681","article-title":"PET imaging\u2013based evaluation of hepatobiliary transport in humans with (15R)-11C-TIC-Me","volume":"53","author":"Takashima","year":"2012","journal-title":"J. Nucl. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1208\/s12248-019-0323-0","article-title":"Towards improved pharmacokinetic models for the analysis of transporter-mediated hepatic disposition of drug molecules with positron emission tomography","volume":"21","author":"Karch","year":"2019","journal-title":"AAPS J."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1016\/j.jhep.2017.02.023","article-title":"Hepatobiliary transport kinetics of the conjugated bile acid tracer 11C-CSar quantified in healthy humans and patients by positron emission tomography","volume":"67","author":"Munk","year":"2017","journal-title":"J. Hepatol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.1023\/A:1018943613122","article-title":"Physiological parameters in laboratory animals and humans","volume":"10","author":"Davies","year":"1993","journal-title":"Pharm. Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/0378-5173(91)90345-O","article-title":"Pharmacokinetics of diltiazem and deacetyldiltiazem in rats","volume":"76","author":"Lee","year":"1991","journal-title":"Int. J. Pharm."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1038\/clpt.2013.85","article-title":"Imaging in the study of membrane transporters","volume":"94","author":"Kusuhara","year":"2013","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Chen, M., and Will, Y. (2018). Noninvasive preclinical and clinical imaging of liver transporter function relevant to drug-induced liver injury. Drug-Induced Liver Toxicity, Springer. Methods in Pharmacology and Toxicology.","DOI":"10.1007\/978-1-4939-7677-5"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1097\/FTD.0000000000000381","article-title":"A Time-dependent model describes methotrexate elimination and supports dynamic modification of MRP2\/ABCC2 activity","volume":"39","author":"Woillard","year":"2017","journal-title":"Ther. Drug Monit."},{"key":"ref_43","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_44","doi-asserted-by":"crossref","first-page":"1082","DOI":"10.1208\/s12248-013-9514-2","article-title":"Effects of selected OATP and\/or ABC transporter inhibitors on the brain and whole-body distribution of glyburide","volume":"15","author":"Tournier","year":"2013","journal-title":"AAPS J."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2745","DOI":"10.1021\/mp500027c","article-title":"PET imaging of oatp-mediated hepatobiliary transport of [11C]rosuvastatin in the rat","volume":"11","author":"He","year":"2014","journal-title":"Mol. Pharm."},{"key":"ref_46","first-page":"48","article-title":"Quantification of hepatobiliary function as an integral part of imaging with technetium-99m-mebrofenin in health and disease","volume":"32","author":"Doo","year":"1991","journal-title":"J. Nucl. Med."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"944","DOI":"10.1124\/pr.113.007518","article-title":"Transporters and drug-drug interactions: Important determinants of drug disposition and effects","volume":"65","author":"Fromm","year":"2013","journal-title":"Pharmacol. Rev."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1002\/cpt.437","article-title":"Transport vs. metabolism: What determines the pharmacokinetics (PK) and pharmacodynamics (PD) of drugs? Insights from the extended clearance model","volume":"100","author":"Unadkat","year":"2016","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1267","DOI":"10.2967\/jnumed.108.059162","article-title":"Imaging of cyclosporine inhibition of P-Glycoprotein activity using 11C-verapamil in the brain: Studies of healthy humans","volume":"50","author":"Muzi","year":"2009","journal-title":"J. Nucl. Med."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"82","DOI":"10.2967\/jnumed.114.146894","article-title":"Increased permeability-glycoprotein inhibition at the human blood-brain barrier can be safely achieved by performing PET during peak plasma concentrations of tariquidar","volume":"56","author":"Kreisl","year":"2015","journal-title":"J. Nucl. Med."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"985","DOI":"10.2967\/jnumed.118.219972","article-title":"Impact of P-glycoprotein function on the brain kinetics of the weak substrate 11C-metoclopramide assessed with PET imaging in humans","volume":"60","author":"Tournier","year":"2019","journal-title":"J. Nucl. Med."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/12\/6\/486\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:33:12Z","timestamp":1760175192000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/12\/6\/486"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,5,27]]},"references-count":51,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2020,6]]}},"alternative-id":["pharmaceutics12060486"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics12060486","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,5,27]]}}}