Evidence of Transport Protein Regulations in the Intestine and Kidney of the Rat with Obstructive Cholestasis: A Potential Therapeutic Target for Maintaining Digoxin Clearance

The main route of elimination of digoxin is renal excretion, which is closely correlated with glomerular filtration rate and combined with tubular secretion and reabsorption. Drugs like digoxin, which undergo biliary elimination, may experience reduced clearance in patients with obstructive cholestasis. This study aims to better understand the impact of extrahepatic cholestasis on the regulation of membrane transporters involved in digoxin processing and its implications for digoxin clearance. Digoxin injection solution was purchased from Baxter Healthcare Corporation (Deerfield, IL, United States). Twelve adult rats were randomly assigned to either a bile duct ligation (BDL) group or a sham group (n=6). Hepatic and renal laboratory values, along with digoxin pharmacokinetic (PK) studies, were conducted before and 7 days after BDL or the sham procedure. Afterward, the animals were sacrificed, and tissue samples were collected to assess the expression of cell membrane transport proteins using quantitative western blot and real-time PCR. The study found that digoxin clearance was significantly reduced, and liver function was impaired in BDL rats, though renal function remained unaffected. BDL led to increased MDR1 expression in the liver and kidney, while MDR1 expression decreased in the small intestine. Additionally, OATP1A4 expression was up-regulated in the liver but down-regulated in the intestine after BDL, and OATP4C1 expression significantly increased in the kidney. These findings suggest that membrane transporters involved in digoxin processing are regulated during extrahepatic cholestasis, favoring increased digoxin excretion by the kidney and reduced absorption from the intestine to compensate for the decreased clearance caused by cholestasis. This insight could be clinically relevant, suggesting that modifying transporter activities through pharmaceutical interventions might improve digoxin clearance during cholestasis.