Phase II metabolism

An enzymatic reaction in which a conjugation step is carried out on a drug or on a phase I metabolite. This often involves addition of a large water-soluble sugar group, or sulphate group, to a suitable oxygen or nitrogen group on the drug or metabolite. The conjugate is then more easily excreted in the urine, although if the molecular weight of the conjugate is greater than around 400 g/mol (which is common with glucuronides), then secretion in the bile into the large intestine is also possible. The conjugate would then be excreted in the faeces.

O-Glucuronide conjugates (a glucuronic acid attached to an oxygen atom on the drug) secreted in bile into the intestines can then be exposed to intestinal bacteria that express glucuronidase enzymes. These enzymes can cleave the bond between the drug and the glucuronic acid moiety, leaving a hydroxyl group on the drug at the cleavage point. This cleaved drug molecule may be identical to the parent drug (if the drug originally contained a hydroxyl group that was conjugated directly by glucuronosyl transferase) or to the phase I hydroxylated metabolite of the parent drug. In the absence of the large, hydrophilic glucuronic acid conjugating group, the cleaved drug (or phase I metabolite) can be reabsorbed from the GI tract, reach the systemic circulation and distribute back to the target tissues. This process, referred to as enterohepatic recirculation, can extend the life of the drug in the body, slowing clearance and extending the elimination half-life.