5.8 : Phase II Reactions: Glucuronidation

Glucuronidation, a pivotal phase II biotransformation process, involves the coupling of glucuronic acid to a drug or xenobiotic. Given its widespread occurrence and critical role in drug metabolism, it's considered the most crucial phase II reaction. It enhances the water solubility of substances, aiding their expulsion from the body. The driving force behind these reactions is a group of enzymes known as UDP-glucuronosyltransferases (UGTs). UGTs facilitate the transfer of a glucuronic acid moiety from UDP-glucuronic acid to the substrate, forming a glucuronide conjugate. This conjugate, being more polar, is swiftly excreted by the kidneys.

The formation of glucuronide involves multiple steps. Initially, the UGT enzyme binds to both the substrate and UDP-glucuronic acid. Following this, the glucuronic acid moiety is transferred to a functional group on the substrate, such as a hydroxyl (–OH), amine (–NH₂), thiol (–SH), or carboxyl (–COOH) group, resulting in a glucuronide metabolite. Depending on the site of conjugation, there are various types of glucuronides. O-glucuronides involve the attachment of glucuronic acid with a hydroxyl group, N-glucuronides with an amine group, S-glucuronides with a thiol group, and C-glucuronides with a carbon atom.

Several commonly used drugs, such as acetaminophen, morphine, and ibuprofen, undergo glucuronidation. For instance, acetaminophen is metabolized into a glucuronide conjugate before urinary excretion. Morphine transforms into morphine-3-glucuronide, a polar and less active metabolite, while ibuprofen is metabolized into an inactive glucuronide conjugate. In addition to these, antidepressants like amitriptyline and HIV medications such as raltegravir also undergo glucuronidation. This reaction plays a significant role in metabolizing various drugs across different therapeutic classes, ensuring their effective elimination and reducing their potential toxicity.