effect of enterohepatic circulation on drug half-life

directory of Chem Help ASAP videos: https://www.chemhelpasap.com/youtube/

In a discovery program, the research team studies early compounds with in vitro ADME studies. Promising compounds will have good solubility, good membrane permeability, and reasonable metabolic stability in metabolic stability assays. Based on these data, the research group will have enough information to make an educated prediction on the half-life of the compound in preclinical species. These predictions always have uncertainty to them. Even so, compounds rarely show a half-life that is much longer than the prediction – a surprisingly long half-life. How can a compound show a far longer half-life than the metabolic stability assays predict? Well, there is an explanation.
That explanation is enterohepatic circulation, sometimes called enterohepatic recirculation. So, the compound enters the patient or animal by the mouth. We’ll assume we have oral administration. The compound goes into the GI tract. Since we know it has good membrane permeability, absorption will not be an issue. Once the compound traverses the liver, it reaches the general circulation. As the drug passes through the liver, it can be metabolized. Many metabolites, especially phase II conjugates, are polar and excreted via biliary excretion, through the gall bladder. Here is where it gets interesting. Bacteria in the gut can sometimes cleave the conjugated group from the metabolite to restore the unconjugated drug form – restore the parent drug. The unconjugated form can then be reabsorbed from the small intestine, make it back to general circulation, and lead to higher drug exposure in the patient. So, while the liver is clearing the drug as expected and as predicted by metabolic stability assays, the excreted metabolites may be recycled into unchanged drug. The same drug molecules may therefore need to be cleared multiple times before they can be completed excreted in the feces. Let’s see an example.
Ethchlorvynol is a sedative. Through the OH of the alcohol, the compound undergoes phase II metabolism – glucuronidation – to form the metabolite on the right. This metabolite, the glucuronide, undergoes biliary excretion and enters the small intestine. In the gut, bacteria cleave the glucuronic acid group, reform the parent drug, ethchlorvynol, and the drug is reabsorbed to repeat the process again. This is enterohepatic circulation, and it can greatly extend the predicted half-life of a drug.