Regulations of cell membrane transport proteins in rats with obstructive cholestasis: an implication of potential therapeutic target for maintaining digoxin clearance

Author(s): Parker J Giroux, Hannah L. Bell, Benjamin Billingsley, Emily Pickich, and Hua Liu

Drugs, such as digoxin, that undergo biliary elimination may have a decreased clearance in patients with obstructive cholestasis. The current study is to better understand the effect of extrahepatic cholestasis on regulations of membrane transporters involving digoxin and its implication for digoxin clearance. Twelve adult rats were randomly divided into bile duct ligation (BDL) and sham groups (n=6). Hepatic and renal laboratory values and digoxin pharmacokinetic (PK) studies were established before and 7 days after BDL or a sham procedure. Then, animals were sacrificed and tissue samples were taken to determine the expressions of cell membrane transport proteins by quantitative western blot and real-time PCR. Digoxin clearance was significantly decreased and liver function, but not renal function, was impaired in BDL rats. BDL resulted in increased MDR1 expression in the liver and kidney and decreased MDR1 expression the small intestine. OATP1A4 was up-regulated in the liver but down-regulated in the intestine after BDL. Expression of OATP4C1 was significantly increased in the kidney following BDL. The results suggest that cell membrane transporters of digoxin are regulated during extrahepatic cholestasis. These regulations are favorable for increasing digoxin excretion in the kidney and decreasing its absorption from the intestine to compensate for reduced digoxin clearance due to cholestasis.

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