ABSTRACT
Conjugation pathways involve the addition of a hydrophilic group such as glucuronic acid to a drug, and the mechanism involves an enzyme and a cofactor that is the source of this hydrophilic group. Glucuronidation is the most common conjugation pathway, both because of the range of substrates that can undergo glucuronidation and because it is often a quantitatively important pathway. Glucuronidation is usually a low-affinity, high-capacity system. Acetylation decreases the polarity of a drug rather than increasing it, but the substrates, e.g., aromatic amines, hydroxylamines, and hydrazines, are often toxic, and acetylation usually decreases this toxicity. Glutathione conjugates are often converted to mercapturic acids before excretion in urine. The number of drugs susceptible to S-methylation is limited but greater than the number turned over by catechol-O-methyltransferase (COMT). N-methyltransferase, active toward histamine and the catechol neurotransmitters, e.g., norepinephrine, is even more restrictive than COMT in terms of the metabolism of exogenous compounds.
