Drug Metabolism: Phase II Reactions

Phase II metabolism involves two primary conjugation reactions: sulfation and glucuronidation. Both reactions attach endogenous molecules to parent drugs or phase I metabolites, producing more hydrophilic drug conjugates. These conjugation reactions typically generate biologically inactive metabolites, though certain prodrugs may form active metabolites instead.

Glucuronidation occurs at the luminal side of the endoplasmic reticulum. The enzyme UDP-glucuronyl transferase catalyzes the transfer of glucuronic acid from an activated endogenous cofactor to the substrate's reactive functional group. The resulting high molecular weight metabolites are typically excreted through bile.

Sulfation occurs in the cytosol, whereas glucuronidation occurs at the endoplasmic reticulum. Sulfation uses phosphoadenosyl phosphosulfate as the activated cofactor and requires the sulfotransferase enzyme to transfer a sulfate group to the substrate. Both reactions increase drug hydrophilicity but operate in different cellular compartments.

Phosphoadenosyl phosphosulfate (PAPS) is an activated endogenous cofactor formed during sulfation reactions. It transfers a sulfate group to the reactive site on the drug substrate in the presence of the sulfotransferase enzyme. This sulfate conjugation makes drugs more hydrophilic and facilitates their elimination from the body.

Phase II conjugation reactions attach polar endogenous molecules like glucuronic acid or sulfate groups to drugs, increasing their water solubility. This increased hydrophilicity prevents drugs from being reabsorbed in the kidneys and facilitates their excretion through bile or urine, promoting drug elimination from the body.

While most phase II conjugation reactions produce biologically inactive metabolites, certain prodrugs can form active metabolites through sulfation or glucuronidation. This means that in some cases, the conjugated metabolite retains or gains pharmacological activity, making phase II metabolism clinically significant beyond simple detoxification.

Phase II metabolites have high molecular weights due to conjugation with endogenous molecules, making them too large for passive reabsorption. Glucuronidated metabolites are primarily excreted in bile, while sulfated metabolites may be excreted through renal or biliary routes, depending on their molecular size and properties.