Metabolism of drugs by leukocytes.

Neutrophils and monocytes can metabolize drugs to reactive metabolites, especially those drugs that have nitrogen or sulfur in a low oxidation state. The major system involved in this oxidation is the combination of NADPH oxidase and myeloperoxidase which generates HOCl. Although this system is unlikely to be quantitatively important, i.e. it is unlikely to have a significant effect on the pharmacokinetics of a drug, the reactive metabolites produced appear to have significant biological effects. Reactive metabolites, by their very nature, have short half-lives, and most of their effects will be exerted on the cells that formed them. Therefore, they are likely to be important for adverse reactions that involve leukocytes, such as agranulocytosis and immune-mediated reactions. However, the mechanism of these reactions is unknown and evidence for the association of leukocyte-derived reactive metabolites with such reactions is circumstantial at present. There is also circumstantial evidence to link the formation of such reactive metabolites to the antiinflammatory effects of some drugs. Possible mechanisms include the scavenging of other reactive species or inhibition of cells, especially neutrophils and macrophages, involved in inflammation. The oxidation of drugs by leukocytes requires activation of the cells; therefore, infection or other inflammatory conditions that activate leukocytes may represent one of the risk factors for idiosyncratic drug reactions.