Exploring the Role of MASH Induced Transporter Alterations in Pharmacokinetics and Therapeutic Efficacy

Abstract

Metabolic dysfunction-associated steatohepatitis (MASH), formerly known as nonalcoholic steatohepatitis (NASH), is a progressive form of metabolic dysfunction-associated fatty liver disease (MAFLD) characterized by steatosis, inflammation, and fibrosis. With MAFLD affecting up to 50% of the global population and as many as 30% of cases progressing to MASH, it has emerged as a leading cause of chronic liver disease. While lifestyle factors contribute to its onset, MASH pathogenesis is complex, involving systemic metabolic dysfunction, hepatocellular stress, and dysregulated immune responses. Beyond driving progressive liver injury, MASH also disrupts drug disposition by altering the expression and function of hepatic and renal transporters, leading to altered pharmacokinetics, ineffective therapy, or increased toxicity. In the liver, MASH is associated with impaired canalicular localization of multidrug resistance-associated protein 2 (MRP2), which reduces biliary efflux of conjugated drug metabolites, and upregulation of sinusoidal efflux transporters such as MRP3, which redirects metabolites into systemic circulation. Concurrently, reduced expression of organic anion transporting polypeptide 1B3 (OATP1B3) limits hepatic uptake of circulating substrates. Collectively, these changes redistribute drugs and metabolites away from biliary elimination toward systemic retention, with important implications for efficacy and toxicity. MASH also perturbs renal drug handling. Experimental models demonstrate reduced glomerular filtration and altered transporter expression, including downregulation of organic anion transporters 3 (OAT3) and 4 (OAT4), and trends toward decreased MRP4 expression. These changes impair uptake and clearance of transporter substrates such as valsartan, adefovir, and ezetimibe-glucuronide, resulting in systemic accumulation. MASH frequently coexists with obesity, type 2 diabetes, and dyslipidemia, conditions that accelerate disease progression and increase polypharmacy. Many therapies for these comorbidities, including statins, antivirals, and anticancer agents, rely on OATP-mediated hepatic uptake and MRP-mediated efflux for clearance, making transporter dysregulation especially relevant. Dysregulation of renal transporters, including OATs and MRPs, further exacerbates systemic drug exposure and toxicity. While liver disease is widely recognized to negatively influence the safety of existing therapeutics, this dissertation focuses on the role of hepatic and renal transporter dysregulation in MASH, investigating how these changes alter drug disposition and provide opportunities for biomarker-guided improvements in diagnosis and patient stratification. The studies presented herein demonstrate the impact of MASH-induced transporter changes on drug disposition and highlight the potential for leveraging these alterations to advance precision medicine and biomarker discovery.