Hepatic Drug Excretion: Enterohepatic Cycling

Enterohepatic cycling occurs when the liver releases bile-containing drugs into the duodenum, where they can be reabsorbed into the bloodstream instead of being excreted in feces. This process prolongs the drug's activity and systemic levels. For conjugated metabolites like glucuronides, reabsorption requires enzymatic hydrolysis by intestinal microflora, extending the drug's presence in the body before elimination.

Transporters in the hepatocyte membrane actively move drugs into or out of cells, adding them to bile secretions. These transporters are located in the canalicular membrane and are essential for the active secretion of drugs and metabolites into bile. This transport mechanism is an integral part of the digestive process, releasing substances into the gastrointestinal tract for potential elimination or reabsorption.

Bile produced by hepatocytes moves through internal bile ducts, eventually merging into the common hepatic duct. It becomes concentrated in the gallbladder and is subsequently released through the cystic duct into the common bile duct, which carries it to the duodenum. This pathway allows bile-containing drugs and metabolites to enter the gastrointestinal tract.

Leflunomide, an anti-rheumatoid arthritis drug, undergoes enterohepatic cycling, which causes elevated systemic drug levels. To mitigate potential toxic effects from this prolonged circulation, cholestyramine or activated charcoal is used to bind the active drug in the intestines, preventing reabsorption and enhancing drug elimination through feces.

Drugs undergoing enterohepatic cycling may exhibit a small secondary peak in the plasma drug-concentration curve, indicating reabsorption of biliary-excreted drugs. High drug doses can result in saturation of the biliary secretion process, altering the plasma level-time curve. This phenomenon becomes particularly important after administering multiple or very high drug doses.

Bile duct cannulation in animal studies and drug recovery from feces in humans provide estimates of biliary excretion. These methods help researchers quantify the extent to which drugs and metabolites are secreted into bile and subsequently eliminated. Fecal drug recovery is particularly useful for assessing unabsorbed drugs and biliary excretions expelled from the body.

Intestinal microflora perform enzymatic hydrolysis of conjugated metabolites like glucuronides, enabling their reabsorption into the bloodstream. This microbial activity is essential for converting conjugated forms back to active compounds that can be reabsorbed, thereby extending the drug's presence in the body and perpetuating the enterohepatic cycling process.