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However, limited knowledge exists on how MASH may alter statin disposition within hepatocytes where the statin target, 3\u2010hydroxy\u20103\u2010methylglutaryl coenzyme A (HMG\u2010CoA) reductase, is located. This study used a physiologically based pharmacokinetic (PBPK)\/permeability\u2010limited multicompartment liver (PerMCL) framework, incorporating zonal transporter and drug\u2010metabolizing enzyme data. Systemic and hepatocellular concentrations of pravastatin, rosuvastatin, and atorvastatin were simulated in Healthy Volunteers (HV), Obese, Morbidly Obese, and MASH virtual populations with the Simcyp Simulator. A pharmacodynamic model in Simcyp Designer was then used to simulate alterations in rosuvastatin cholesterol\u2010lowering efficacy between these populations. Hepatic transport and metabolism pathways were verified against clinical data. Organic anion transporting polypeptide (OATP)1B model uptake pathways were verified using genotype and drug\u2013drug interaction data. Atorvastatin metabolism pathways were verified using metabolite data. Steady\u2010state plasma and zonal hepatocellular concentration\u2013time profiles for each statin were simulated across virtual populations of 100 individuals aged 40\u201365\u2009years. Simulations predicted &gt;\u200970% increases in maximal total plasma concentrations and area under the curve for pravastatin and rosuvastatin in MASH compared to HV, with changes in these parameters for atorvastatin simulated to increase &gt;\u2009250%. In MASH, unbound hepatocellular exposure increased by up to 127% in the periportal region for atorvastatin and decreased by up to 55% in the pericentral region for rosuvastatin. The pharmacodynamic model simulated decreased rosuvastatin cholesterol\u2010lowering efficacy in MASH compared with Obese, which could be compensated for with a 50% increase in dose according to exploratory simulations.<\/jats:p>","DOI":"10.1002\/psp4.70138","type":"journal-article","created":{"date-parts":[[2025,11,13]],"date-time":"2025-11-13T11:12:23Z","timestamp":1763032343000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Impact of Obesity and\n                    <scp>MASH<\/scp>\n                    on Zonal Hepatocellular Statin Exposure: Pharmacodynamic Insights From a Permeability\u2010Limited Multicompartment Liver Model"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7476-9248","authenticated-orcid":false,"given":"William A.","family":"Murphy","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\/0000-0001-6960-7757","authenticated-orcid":false,"given":"Noora","family":"Sj\u00f6stedt","sequence":"additional","affiliation":[{"name":"Division of Pharmaceutical Biosciences, Faculty of Pharmacy University of Helsinki  Helsinki Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5460-4350","authenticated-orcid":false,"given":"Mailys De Sousa","family":"Mendes","sequence":"additional","affiliation":[{"name":"Certara UK Ltd. Certara Predictive Technologies, Simcyp Division  Sheffield UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5082-0168","authenticated-orcid":false,"given":"Mattie","family":"Hartauer","sequence":"additional","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\/0000-0003-1945-4929","authenticated-orcid":false,"given":"Kim L. 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