3.18:
Drug Metabolism: Phase II Reactions
In phase II reactions, parent drugs or phase I metabolites, bearing suitable functional groups, react with endogenous molecules to produce more hydrophilic drug conjugates.
The two main conjugation reactions, sulfation and glucuronidation, often generate biologically inactive metabolites. However, in the case of certain prodrugs, active metabolites may be formed.
Glucuronidation occurs at the luminal side of the endoplasmic reticulum. The reaction involves an activated high-energy endogenous cofactor, from which glucuronic acid gets transferred to the reactive functional group on the substrate in the presence of UDP-glucuronyl transferase.
The metabolites produced have high molecular weights and are therefore excreted in bile.
Sulfation occurs in the cytosol. The reaction involves the formation of an active endogenous cofactor, phosphoadenosyl phosphosulfate, which transfers a sulfate group to the reactive handle on the substrate in the presence of the sulfotransferase enzyme.
3.18:
Drug Metabolism: Phase II Reactions
Phase II reactions are essential for the detoxification and elimination of drugs from the body. These reactions involve the conjugation of parent drugs or their phase I metabolites with endogenous molecules, resulting in more hydrophilic drug conjugates. The primary conjugation reactions in this phase are sulfation and glucuronidation. Both sulfation and glucuronidation typically produce biologically inactive metabolites. However, in some cases involving prodrugs, active metabolites may be formed. Glucuronidation occurs at the luminal side of the endoplasmic reticulum. This process requires an activated endogenous cofactor, which transfers glucuronic acid to the substrate's reactive functional group. The enzyme responsible for facilitating this transfer is UDP-glucuronyl transferase. The resulting metabolites have high molecular weights and are typically excreted through bile. Sulfation, on the other hand, takes place within the cytosol of the cell. This reaction involves the formation of an active endogenous cofactor called phosphoadenosyl phosphosulfate (PAPS). PAPS transfers a sulfate group to the substrate's reactive site in the presence of the sulfotransferase enzyme.