Antigen-presenting cells recognize complex, three-dimensional protein molecules of at least 1,000 Daltons (Da) in size. Most drugs are much smaller than this, and cannot be recognized on their own. Only proteins such as insulin or exogenous sera are identified and their peptides presented directly to T cells.

Drugs that are chemically reactive may bond covalently to body proteins, altering them and forming large enough molecules for antigen-presenting cells to recognize. This process is called haptenation, and the smaller reactive molecule, a hapten. Some other drugs are inert until they are partially metabolized (prohaptens), and their breakdown products bind native proteins to serve as antigens. Metabolic variations in some patients may produce more active haptens, or prevent these fragments from being detoxified, causing them to accumulate and make binding proteins more likely.

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