Parent drugs or their Phase I metabolites that contain suitable chemical groups often undergo coupling or conjugation reactions with an endogenous substance to yield drug conjugates. In general, conjugates are polar molecules that are readily excreted and often inactive. Conjugate formation involves high-energy intermediates and specific transfer enzymes. Such enzymes (transferases) may be located in microsomes or in the cytosol. They catalyze the coupling of an activated endogenous substance (such as the uridine 5'-diphosphate [UDP] derivative of glucuronic acid) with a drug (or endogenous compound), or of an activated drug (such as the S-CoA derivative of benzoic acid) with an endogenous substrate. Because the endogenous substrates originate in the diet, nutrition and disease play critical roles in the regulation of drug conjugations.

Drug conjugations were once believed to represent terminal inactivation events and as such have been viewed as "true detoxification" reactions. However, this concept must be modified, since it is now known that certain conjugation reactions (0-sulfation of N-hydroxyacetylaminofluorene and N-acetylation of isoniazid) may lead to the formation of reactive species responsible for the hepatotoxicity of the drug.