Adverse Drug Effect—Reactive Metabolites and Idiosyncratic Drug Reactions: Part I

IDIOSYNCRATIC DRUG REACfIONS occur in few patients (<0.1 percent), but may present serious medical problems depending on how widely the drug is used and the severity of the reaction. Idiosyncratic reactions are unpredictable and therefore virtually impossible to prevent. Moreover, they are frequently life-threatening. Uetrecht observed that "idiosyncratic reactions pose a major problem for the development of new drugs. They are not detected by toxicology testing in animals or in early clinical testing."! The list of drugs brought to the marketplace before the potential for idiosyncratic reactions was recognized includes practolol, benoxaprofen, ticrynafen, zomepirac, and nomifensine. Each of these drugs was subsequently withdrawn. The most common clinical manifestations of idiosyncratic drug reactions are fever, lymphadenopathy, skin rash, and/or organ involvement; the kidneys, liver, lungs, bone marrow, peripheral blood cells, heart, and serous membranes, such as those in joints and pleura, may be affected. Most idiosyncratic reactions are characterized by " ...a requirement for either prior exposure to the drug or a lag period of more than a week between starting the drug and the development of toxicity." Still another characteristic is the immediate recurrence of symptoms when a patient who has had an idiosyncratic reaction is reexposed to the offending drug.1 Many idiosyncratic drug reactions appear to have an allergic nature, suggesting the involvement of the immune system. According to Uetrecht, " ...with few exceptions, a molecule must have a molecular weight of greater than 1000 in order to be antigenic. Very few drugs are this large, and if they are to be antigenic they must be bound to other macromolecules.... It also appears as if a covalent bond between drug and protein is required for antigenicity." He went on to point out that with few exceptions"...drugs are not sufficiently reactive to form a covalent bond to protein. However, many drugs are metabolized to chemically reactive species, which can form a covalent bond...."1 According to Riley et aI., "These reactive species are commonly products of Phase I oxidation reactions mediat-