Many drugs interact with plasma or tissue proteins or with other macromolecules, such as melanin and DNA, to form a drug–macromolecule complex. The formation of a drug protein complex is often named drug–protein binding. Drug–protein binding may be a reversible or an irreversible process. Irreversible drug–protein binding is usually a result of chemical activation of the drug, which then attaches strongly to the protein or macromolecule by covalent chemical bonding. Irreversible drug binding accounts for certain types of drug toxicity that may occur over a long time period, as in the case of chemical carcinogenesis, or within a relatively short time period, as in the case of drugs that form reactive chemical intermediates. For example, the hepatotoxicity of high doses of acetaminophen is due to the formation of reactive metabolite intermediates that interact with liver proteins.

Most drugs bind or complex with proteins by a reversible process. Reversibledrug–protein binding implies that the drug binds the protein with weaker chemical bonds, such as hydrogen bonds or van der Waals forces. The amino acids that compose the protein chain have hydroxyl, carboxyl, or other sites available for reversible drug interactions.