Altered renal disposition of adefovir in metabolic dysfunction-associated steatohepatitis using the fast-food diet and thioacetamide-induced model to extrapolate renal secretion.

Metabolic dysfunction-associated fatty liver disease and metabolic dysfunction-associated steatohepatitis (MASH) are the most prevalent liver diseases globally. As MASH progresses, changes in expression of xenobiotic transporters significantly alter drug disposition and subsequent increased risk of toxicity. Patients with MASH and co-occurring chronic hepatitis B virus are becoming increasingly prevalent, presenting a unique challenge in clinical practice. Adefovir (ADEF) is an antiviral drug used to treat hepatitis B virus infection and is a substrate of organic anion transporters (OATs). Using a fast-food diet and thioacetamide-induced (FFDTH) MASH model that reflects human OAT expression, we evaluated the effect of MASH on the disposition of ADEF (7 mg/kg retro-orbital). FFDTH mice exhibited characteristic hepatic macrosteatosis, hepatocyte ballooning, lobular inflammation, weight loss, and had elevated liver to body weight ratios, but there were no signs of kidney injury, such as inflammation or fibrosis. Renal OAT 3 expression in FFDTH mice was decreased, with reduced uptake of ADEF by proximal tubule cells and increased plasma retention. Elimination into the urine was decreased compared to healthy mice, due in part to decreased expression of both Mrp4 and Oat5. Glomerular filtration rate was also decreased in FFDTH mice, which could further explain the change in ADEF disposition. Despite these changes, no significant difference in hepatic or renal accumulation was observed. These data suggest that renal disposition of ADEF may be altered in humans with MASH due to the similarity of OAT transporter expression in the FFDTH model of MASH. SIGNIFICANCE STATEMENT: As metabolic liver disease and chronic hepatitis B increasingly coexist, understanding how metabolic dysfunction-associated steatohepatitis alters drug handling is critical for patient safety. The study findings demonstrate that metabolic dysfunction-associated steatohepatitis significantly impairs renal transporter-mediated elimination of adefovir, highlighting the need to consider altered kidney drug disposition and potential dose adjustments in this growing patient population.