Effects of Liver Surgery on Drug Transporters in the Liver and Remote Organs.

Abstract

Alterations in drug transporters in acute liver failure and chronic liver diseases, such as cirrhosis, have been reviewed before. However, there is a lack of comprehensive reviews on how liver surgery, including transplantation and partial hepatectomy, affects drug transporters. Because ischemia-reperfusion (IR) injury is a hallmark of liver transplantation and most other surgical procedures of the liver, this review focuses on the effects of IR injury, in addition to liver resection, on the expression and function of transporters in the liver and remote organs. Most of the reported studies in this area are carried out in animal models of liver surgeries, with relatively limited data in humans. The results indicate that the effects of IR injury and partial hepatectomy on drug transporters are complex and depend on many variables, such as the species, length and type of ischemia, reperfusion time, and the extent of liver resection. However, for a few major transporters, clear trends have emerged based on both animal and human studies. A major trend is that warm (normothermic) hepatic IR injury or liver transplantation causes overexpression of P-glycoprotein in the liver and remote organs, affecting the pharmacokinetics of substrate drugs. Another observed trend is the relocalization of the liver MRP2/Mrp2 from the canalicular membranes to the cytoplasmic area, reducing the function of the transporter even in the absence of a change in its protein. Alterations in transporter function, such as P-glycoprotein, may significantly impact the pharmacokinetics and pharmacodynamics of drugs in patients undergoing liver surgeries.