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The aim of this study was to build a physiologically\u2010based pharmacokinetic (PBPK) model to predict drug exposure in NASH by incorporating NASH\u2010related changes in hepatic transporters. Morphine and morphine\u20103\u2010glucuronide (M3G) were used as model compounds. A PBPK model of morphine with permeability\u2010limited hepatic disposition was extended to include M3G disposition and enterohepatic recycling (EHR). The model captured the area under the plasma concentration\u2010time curve (AUC) of morphine and M3G after intravenous morphine administration within 0.82\u2010fold and 1.94\u2010fold of observed values from 3 independent clinical studies for healthy adult subjects (6, 10, and 14 individuals). When NASH\u2010related changes in multidrug resistance\u2010associated protein 2 (MRP2) and MRP3 were incorporated into the model, the predicted M3G mean AUC in NASH was 1.34\u2010fold higher compared to healthy subjects, which is slightly lower than the observed value (1.63\u2010fold). Exploratory simulations on other physiological changes occurring in NASH (e.g., moderate decreases in glomerular filtration rate and portal vein blood flow) revealed that the effect of transporter changes was most prominent. Additionally, NASH\u2010related transporter changes resulted in decreased morphine EHR, which could be important for drugs with extensive EHR. This study is an important first step to predict drug disposition in complex diseases such as NASH using PBPK modeling.<\/jats:p>","DOI":"10.1002\/cpt.2037","type":"journal-article","created":{"date-parts":[[2020,9,14]],"date-time":"2020-09-14T07:56:28Z","timestamp":1600070188000},"page":"676-687","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Physiologically\u2010Based Pharmacokinetic Model of Morphine and Morphine\u20103\u2010Glucuronide in Nonalcoholic Steatohepatitis"],"prefix":"10.1111","volume":"109","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6960-7757","authenticated-orcid":false,"given":"Noora","family":"Sj\u00f6stedt","sequence":"first","affiliation":[{"name":"Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy University of North Carolina at Chapel Hill Chapel Hill North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8809-1960","authenticated-orcid":false,"given":"Sibylle","family":"Neuhoff","sequence":"additional","affiliation":[{"name":"Simcyp\u2010Division Certara UK Ltd. 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