phase II metabolism

If phase I exposes a chemical handle, phase II uses that handle to bolt on a large, water-loving tag. Picture attaching a heavy, soggy label to a package so it sinks instead of floats — the drug becomes too polar to slip back across membranes and is shuttled out of the body.

Phase II reactions are conjugations: an enzyme transfers an endogenous group — glucuronic acid, sulfate, glutathione, acetyl, methyl, or an amino acid — onto the drug or its phase I metabolite. Glucuronidation, catalyzed by UDP-glucuronosyltransferases (UGTs), is the most common pathway. The bulky polar conjugate is usually inactive and readily excreted in urine or bile.

Phase II does not always follow phase I; drugs that already carry a suitable group can be conjugated directly. And while conjugates are usually inactive, there are exceptions — morphine-6-glucuronide, for instance, is more potent than morphine itself.