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This recycling also alters drug exposure in the colon, making it critical to establish local concentration for drugs targeting colon (e.g., drugs for colon cancer and inflammatory bowel disease). Methods: In this study, a parent\u2013metabolite middle-out physiologically based pharmacokinetic (PBPK) model was built for genistein and its glucuronide metabolite to estimate the systemic and local exposure of the glucuronide and its corresponding aglycone in rats by incorporating UDP-glucuronosyltransferase (UGT)-mediated metabolism and transporter-dependent glucuronide disposition in the liver and intestine, as well as gut microbial-mediated deglucuronidation that enables the recycling of the parent compound. Results: This parent\u2013metabolite middle-out rat PBPK model utilized in vitro-to-in vivo extrapolated (IVIVE) metabolic and transporter clearance values based on in vitro kinetic parameters from surrogate species, the rat tissue abundance of relevant proteins, and saturable Michaelis\u2013Menten mechanisms. Inter-system extrapolation factors (ISEFs) were used to account for transporter protein abundance differences between in vitro systems and tissues and between rats and surrogate species. Model performance was evaluated at multiple dose levels for genistein and its glucuronide. Model sensitivity analyses demonstrated the impact of key parameters on the plasma concentrations and local exposure of genistein and its glucuronide. Our model was applied to simulate the quantitative impact of glucuronide recycling on the pharmacokinetic profiles in both plasma and colonocytes. Conclusions: Our study underlines the importance of glucuronide recycling in determining local drug concentrations in the intestine and provides a preliminary modeling tool to assess the influence of transporter-mediated drug\u2013drug interactions on glucuronide recycling and local drug exposure, which are often misrepresented by systemic plasma concentrations.<\/jats:p>","DOI":"10.3390\/pharmaceutics17070814","type":"journal-article","created":{"date-parts":[[2025,6,24]],"date-time":"2025-06-24T09:24:18Z","timestamp":1750757058000},"page":"814","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["A Parent\u2013Metabolite Middle-Out PBPK Model for Genistein and Its Glucuronide Metabolite in Rats: Integrating Liver and Enteric Metabolism with Hepatobiliary and Enteroluminal Transport to Assess Glucuronide Recycling"],"prefix":"10.3390","volume":"17","author":[{"given":"Bhargavi Srija","family":"Ramisetty","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Chemistry, The University of Kansas, Lawrence, KS 66047, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rashim","family":"Singh","sequence":"additional","affiliation":[{"name":"Department of Pharmacological and Pharmaceutical Sciences, University of Houston College of Pharmacy, Houston, TX 77204, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2744-6294","authenticated-orcid":false,"given":"Ming","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Pharmacological and Pharmaceutical Sciences, University of Houston College of Pharmacy, Houston, TX 77204, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2494-4172","authenticated-orcid":false,"given":"Michael Zhuo","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, The University of Kansas, Lawrence, KS 66047, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1124\/dmd.32.3.281","article-title":"Glucuronidation and the UDP-glucuronosyltransferases in health and disease","volume":"32","author":"Wells","year":"2004","journal-title":"Drug Metab. Dispos."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1016\/j.cccn.2005.02.023","article-title":"Glucuronidation in therapeutic drug monitoring","volume":"358","author":"Shipkova","year":"2005","journal-title":"Clin. Chim. Acta"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1251","DOI":"10.1097\/ALN.0b013e318238fea0","article-title":"Buprenorphine metabolites, buprenorphine-3-glucuronide and norbuprenorphine-3-glucuronide, are biologically active","volume":"115","author":"Brown","year":"2011","journal-title":"Anesthesiology"},{"key":"ref_4","first-page":"477","article-title":"Morphine-6-glucuronide is more mu-selective and potent in analgesic tests than morphine","volume":"328","author":"Frances","year":"1990","journal-title":"Prog. Clin. Biol. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1086","DOI":"10.1124\/dmd.31.9.1086","article-title":"Isoform selectivity and kinetics of morphine 3- and 6-glucuronidation by human udp-glucuronosyltransferases: Evidence for atypical glucuronidation kinetics by UGT2B7","volume":"31","author":"Stone","year":"2003","journal-title":"Drug Metab. Dispos."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"103316","DOI":"10.1016\/j.drudis.2022.07.001","article-title":"The role of gut microbial beta-glucuronidase in drug disposition and development","volume":"27","author":"Gao","year":"2022","journal-title":"Drug Discov. Today"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1466","DOI":"10.1021\/mp8002557","article-title":"Structure and concentration changes affect characterization of UGT isoform-specific metabolism of isoflavones","volume":"6","author":"Tang","year":"2009","journal-title":"Mol. Pharm."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1264","DOI":"10.2174\/187152012803833107","article-title":"Bioavailability and pharmacokinetics of genistein: Mechanistic studies on its ADME","volume":"12","author":"Yang","year":"2012","journal-title":"Anticancer Agents Med. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e58820","DOI":"10.7554\/eLife.58820","article-title":"Hepatoenteric recycling is a new disposition mechanism for orally administered phenolic drugs and phytochemicals in rats","volume":"10","author":"Tu","year":"2021","journal-title":"eLife"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1146\/annurev.nutr.17.1.353","article-title":"Dietary phytoestrogens","volume":"17","author":"Kurzer","year":"1997","journal-title":"Annu. Rev. Nutr."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1007\/s002030000222","article-title":"Isolation of human intestinal bacteria metabolizing the natural isoflavone glycosides daidzin and genistin","volume":"174","author":"Hur","year":"2000","journal-title":"Arch. Microbiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"8354","DOI":"10.1021\/jf801051d","article-title":"Dose-dependent absorption, metabolism, and excretion of genistein in rats","volume":"56","author":"Zhou","year":"2008","journal-title":"J. Agric. Food Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1007\/s10812-013-9835-z","article-title":"Analysis of Acid-Base Properties of Flavonoid Genistein","volume":"80","author":"Mielczarek","year":"2013","journal-title":"J. Appl. Spectrosc."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1016\/S0014-5793(99)00307-5","article-title":"Daidzein and genistein but not their glucosides are absorbed from the rat stomach","volume":"447","author":"Piskula","year":"1999","journal-title":"FEBS Lett."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.jpba.2010.03.011","article-title":"Simultaneous determination of genistein and its four phase II metabolites in blood by a sensitive and robust UPLC-MS\/MS method: Application to an oral bioavailability study of genistein in mice","volume":"53","author":"Yang","year":"2010","journal-title":"J. Pharm. Biomed. Anal."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"4529","DOI":"10.1021\/jf9039843","article-title":"Absolute bioavailability of isoflavones from soy protein isolate-containing food in female BALB\/c mice","volume":"58","author":"Andrade","year":"2010","journal-title":"J. Agric. Food Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1007\/BF03192335","article-title":"Absolute bioavailability of [14 C] genistein in the rat; plasma pharmacokinetics of parent compound, genistein glucuronide and total radioactivity","volume":"27","author":"Coldham","year":"2002","journal-title":"Eur. J. Drug Metab. Pharmacokinet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1777","DOI":"10.1124\/dmd.105.003673","article-title":"Disposition of flavonoids via recycling: Comparison of intestinal versus hepatic disposition","volume":"33","author":"Chen","year":"2005","journal-title":"Drug Metab. Dispos."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1093\/toxsci\/kfj077","article-title":"Kinetics of genistein and its conjugated metabolites in pregnant Sprague-Dawley rats following single and repeated genistein administration","volume":"90","author":"Soucy","year":"2006","journal-title":"Toxicol. Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.1124\/jpet.108.147371","article-title":"Disposition of Flavonoids via Enteric Recycling: UDP-Glucuronosyltransferase (UGT) 1As Deficiency in Gunn Rats Is Compensated by Increases in UGT2Bs Activities","volume":"329","author":"Wang","year":"2009","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2739","DOI":"10.1111\/bph.13900","article-title":"In vitro-in silico-based analysis of the dose-dependent in vivo oestrogenicity of the soy phytoestrogen genistein in humans","volume":"174","author":"Boonpawa","year":"2017","journal-title":"Br. J. Pharmacol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1007\/s11538-006-9068-x","article-title":"A delayed nonlinear PBPK model for genistein dosimetry in rats","volume":"69","author":"Zager","year":"2007","journal-title":"Bull. Math. Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1111\/j.1539-6924.2006.00743.x","article-title":"Physiologically-based pharmacokinetic modeling of genistein in rats, Part I: Model development","volume":"26","author":"Schlosser","year":"2006","journal-title":"Risk Anal."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2884","DOI":"10.1021\/acs.molpharmaceut.6b00941","article-title":"Transport-Glucuronidation Classification System and PBPK Modeling: New Approach To Predict the Impact of Transporters on Disposition of Glucuronides","volume":"14","author":"Ge","year":"2017","journal-title":"Mol. Pharm."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1124\/jpet.111.180398","article-title":"Quantitative Evaluation of the Impact of Active Efflux by P-Glycoprotein and Breast Cancer Resistance Protein at the Blood-Brain Barrier on the Predictability of the Unbound Concentrations of Drugs in the Brain Using Cerebrospinal Fluid Concentration as a Surrogate","volume":"339","author":"Kodaira","year":"2011","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1458","DOI":"10.1080\/00498254.2019.1572938","article-title":"An evaluation of metabolite profiling of six drugs using dried blood spot","volume":"49","author":"Katyayan","year":"2019","journal-title":"Xenobiotica"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"4355","DOI":"10.1021\/jf0483669","article-title":"Experimental determination of octanol-water partition coefficients of quercetin and related flavonoids","volume":"53","author":"Rothwell","year":"2005","journal-title":"J. Agric. Food Chem."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Liang, C.N., Zhang, Y., Jia, Y., Wang, W.Z., Li, Y.H., Lu, S.K., Jin, J.M., and Tang, S.Y. (2016). Engineering a Carbohydrate-processing Transglycosidase into Glycosyltransferase for Natural Product Glycodiversification. Sci. Rep., 6.","DOI":"10.1038\/srep21051"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.etap.2003.11.008","article-title":"Comparison of Caco-2, IEC-18 and HCEC cell lines as a model for intestinal absorption of genistein, daidzein and their glycosides","volume":"16","author":"Steensma","year":"2004","journal-title":"Environ. Toxicol. Pharmacol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1967","DOI":"10.1002\/mnfr.201500321","article-title":"Establishment and use of new MDCK II cells overexpressing both UGT1A1 and MRP2 to characterize flavonoid metabolism via the glucuronidation pathway","volume":"60","author":"Wang","year":"2016","journal-title":"Mol. Nutr. Food Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1725","DOI":"10.1053\/j.gastro.2009.06.052","article-title":"Targeted metabolomics identifies glucuronides of dietary phytoestrogens as a major class of MRP3 substrates in vivo","volume":"137","author":"Feddema","year":"2009","journal-title":"Gastroenterology"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"261","DOI":"10.2165\/00003088-200847040-00004","article-title":"Evaluation of a Generic Physiologically Based Pharmacokinetic Model for Lineshape Analysis","volume":"47","author":"Peters","year":"2008","journal-title":"Clin. Pharmacokinet."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e0032824","DOI":"10.1128\/aac.00328-24","article-title":"Determining tissue distribution of the oral antileishmanial agent miltefosine: A physiologically-based pharmacokinetic modeling approach","volume":"68","author":"Ramisetty","year":"2024","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1177\/074823379701300401","article-title":"Physiological parameter values for physiologically based pharmacokinetic models","volume":"13","author":"Brown","year":"1997","journal-title":"Toxicol. Ind. Health"},{"key":"ref_35","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_36","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1211\/jpp.60.1.0008","article-title":"Measurements of rat and mouse gastrointestinal pH, fluid and lymphoid tissue, and implications for in-vivo experiments","volume":"60","author":"McConnell","year":"2008","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1083\/jcb.72.2.441","article-title":"Distribution of organelles and membranes between hepatocytes and nonhepatocytes in the rat liver parenchyma. A stereological study","volume":"72","author":"Blouin","year":"1977","journal-title":"J. Cell Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1228","DOI":"10.1124\/jpet.102.046409","article-title":"Metabolism of flavonoids via enteric recycling: Role of intestinal disposition","volume":"304","author":"Chen","year":"2003","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1113\/expphysiol.1989.sp003306","article-title":"The Rat Distal Ileum Has a Reduced Absorptive and Secretory Capacity Compared with Proximal Ileum-Is It to Facilitate Its Chemosensing Function?","volume":"74","author":"Young","year":"1989","journal-title":"Q. J. Exp. Physiol. Transl. Integr."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2826","DOI":"10.1016\/j.xphs.2017.05.003","article-title":"The Constraints, Construction, and Verification of a Strain-Specific Physiologically Based Pharmacokinetic Rat Model","volume":"106","author":"Musther","year":"2017","journal-title":"J. Pharm. Sci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/S0278-6915(00)00136-8","article-title":"Anatomical and physiological parameters affecting gastrointestinal absorption in humans and rats","volume":"39","author":"DeSesso","year":"2001","journal-title":"Food Chem. Toxicol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.cbi.2012.08.016","article-title":"Physiologically based pharmacokinetic model for rats and mice orally exposed to chromium","volume":"200","author":"Kirman","year":"2012","journal-title":"Chem. Biol. Interact."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Ebuzoeme, C., Etim, I., Ikimi, A., Song, J., Du, T., Hu, M., Liang, D., and Gao, S. (2021). Glucuronides Hydrolysis by Intestinal Microbial \u03b2-Glucuronidases (GUS) is Affected by Sampling, Enzyme Preparation, Buffer pH, and Species. Pharmaceutics, 13.","DOI":"10.3390\/pharmaceutics13071043"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2415","DOI":"10.1016\/0006-2952(81)90335-X","article-title":"Intestinal microsomal drug metabolism. A comparison of rat and guinea-pig enzymes, and of rat crypt and villous tip cell enzymes","volume":"30","author":"Dawson","year":"1981","journal-title":"Biochem. Pharmacol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1615\/JEnvironPatholToxicolOncol.2014008425","article-title":"Protective Effect of Acacia Ferruginea against Ulcerative Colitis via Modulating Inflammatory Mediators, Cytokine Profile and NF-\u039aB Signal Transduction Pathways","volume":"33","author":"Sakthivel","year":"2014","journal-title":"J. Environ. Pathol. Toxicol. Oncol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1208\/s12248-010-9209-x","article-title":"Breast Cancer Resistance Protein (BCRP) and Sulfotransferases Contribute Significantly to the Disposition of Genistein in Mouse Intestine","volume":"12","author":"Zhu","year":"2010","journal-title":"Aaps J."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1410","DOI":"10.1039\/C7FO01298E","article-title":"Chemical Inhibition and Stable Knock-down of Efflux Transporters Leads to Reduced Glucuronidation of Wushanicaritin in UGT1A1-Overexpressing HeLa Cells: The Role of Breast Cancer Resistance Protein (BCRP) and Multidrug Resistance-Associated Proteins (MRPs) in the Excretion of Glucuronides","volume":"9","author":"Qin","year":"2017","journal-title":"Food Funct."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1737","DOI":"10.1021\/acs.molpharmaceut.2c00950","article-title":"Quantitative Characterization of Clinically Relevant Drug-Metabolizing Enzymes and Transporters in Rat Liver and Intestinal Segments for Applications in PBPK Modeling","volume":"20","author":"Sharma","year":"2023","journal-title":"Mol. Pharm."},{"key":"ref_49","first-page":"12","article-title":"Distribution of Abcg2 (BCRP) and Abcc2 (MRP2) mRNAs in rat small intestine and liver","volume":"8","author":"Horibe","year":"2009","journal-title":"EXCLI J."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Jarvinen, E., Deng, F., Kiander, W., Sinokki, A., Kidron, H., and Sjostedt, N. (2021). The Role of Uptake and Efflux Transporters in the Disposition of Glucuronide and Sulfate Conjugates. Front. Pharmacol., 12.","DOI":"10.3389\/fphar.2021.802539"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1016\/S0022-3565(24)39291-2","article-title":"Expression and localization of multidrug resistant protein mrp2 in rat small intestine","volume":"293","author":"Mottino","year":"2000","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1007\/s40262-015-0351-6","article-title":"Predicting Drug Extraction in the Human Gut Wall: Assessing Contributions from Drug Metabolizing Enzymes and Transporter Proteins using Preclinical Models","volume":"55","author":"Peters","year":"2016","journal-title":"Clin. Pharmacokinet."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.jphs.2021.10.010","article-title":"Quantitative Prediction of Pharmacokinetic Properties of Drugs in Humans: Recent Advance in in Vitro Models to Predict the Impact of Efflux Transporters in the Small Intestine and Blood\u2013Brain Barrier","volume":"148","author":"Hashimoto","year":"2021","journal-title":"J. Pharmacol. Sci."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1042\/BST20150200","article-title":"Glycosyltransferase Engineering for Carbohydrate Synthesis","volume":"44","author":"McArthur","year":"2016","journal-title":"Biochem. Soc. Trans."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1238","DOI":"10.1002\/jps.20502","article-title":"Physiologically based pharmacokinetic modelling 2: Predicting the tissue distribution of acids, very weak bases, neutrals and zwitterions","volume":"95","author":"Rodgers","year":"2006","journal-title":"J. Pharm. Sci."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.ijpharm.2006.12.046","article-title":"Comparison of oral bioavailability of genistein and genistin in rats","volume":"337","author":"Kwon","year":"2007","journal-title":"Int. J. Pharm."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1002\/psp4.6","article-title":"Sobol Sensitivity Analysis: A Tool to Guide the Development and Evaluation of Systems Pharmacology Models","volume":"4","author":"Zhang","year":"2015","journal-title":"CPT Pharmacomet. Syst. Pharmacol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1675","DOI":"10.1093\/carcin\/bgr188","article-title":"ERbeta-specific agonists and genistein inhibit proliferation and induce apoptosis in the large and small intestine","volume":"32","author":"Schleipen","year":"2011","journal-title":"Carcinogenesis"},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Qi, W., Weber, C.R., Wasland, K., and Savkovic, S.D. (2011). Genistein inhibits proliferation of colon cancer cells by attenuating a negative effect of epidermal growth factor on tumor suppressor FOXO3 activity. BMC Cancer, 11.","DOI":"10.1186\/1471-2407-11-219"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1249","DOI":"10.1124\/dmd.108.020859","article-title":"Closing the gaps: A full scan of the intestinal expression of p-glycoprotein, breast cancer resistance protein, and multidrug resistance-associated protein 2 in male and female rats","volume":"36","author":"MacLean","year":"2008","journal-title":"Drug Metab. Dispos."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"2251","DOI":"10.1021\/ac8024009","article-title":"LC\u2013MS\/MS mediated absolute quantification and comparison of bile salt export pump and breast cancer resistance protein in livers and hepatocytes across species","volume":"81","author":"Li","year":"2009","journal-title":"Anal. Chem."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Gavins, F.K., Dou, L., Qin, Y., Madla, C.M., Murdan, S., Basit, A.W., Mai, Y., and Orlu, M. (2023). Prandial state and biological sex modulate clinically relevant efflux transporters to different extents in Wistar and Sprague Dawley rats. Biomed. Pharmacother., 160.","DOI":"10.1016\/j.biopha.2023.114329"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1124\/dmd.108.023234","article-title":"Absolute difference of hepatobiliary transporter multidrug resistance-associated protein (MRP2\/Mrp2) in liver tissues and isolated hepatocytes from rat, dog, monkey, and human","volume":"37","author":"Li","year":"2009","journal-title":"Drug Metab. Dispos."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"G720","DOI":"10.1152\/ajpgi.00318.2001","article-title":"Expression and localization of the multidrug resistance-associated protein 3 in rat small and large intestine","volume":"282","author":"Rost","year":"2002","journal-title":"Am. J. Physiol.-Gastrointest. Liver Physiol."},{"key":"ref_65","unstructured":"Harbourt, D.E. (2009). An Investigation Into the Role of Glucuronidation on the Disposition and Toxicity of Mycophenolic Acid Using Targeted Quantitative Proteomics. [Ph.D. Thesis, The University of North Carolina at Chapel Hill]."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"2280","DOI":"10.1007\/s11095-016-1966-5","article-title":"Quantification of four efflux drug transporters in liver and kidney across species using targeted quantitative proteomics by isotope dilution NanoLC-MS\/MS","volume":"33","author":"Fallon","year":"2016","journal-title":"Pharm Res-Dordr"}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/17\/7\/814\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:57:22Z","timestamp":1760032642000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/17\/7\/814"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,23]]},"references-count":66,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2025,7]]}},"alternative-id":["pharmaceutics17070814"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics17070814","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,23]]}}}