"We propose that delayed clearance and accumulation of reactive metabolites caused by genetic variants of drug-metabolizing enzymes may be the primary factor, and that immunogenicity, such as the presence of risk HLA alleles and specific T-cell receptor clonotypes in susceptible individuals, may facilitate the development and guide the different types of cutaneous adverse reactions," Dr. Chung and his associates wrote.
Dr. Wen-Hung Chung
However, delayed clearance was also noted in severely affected patients who did not carry the CYP2C9*3 mutation, "suggesting that nongenetic factors such as renal insufficiency, hepatic dysfunction, and concurrent use of substances that compete with or inhibit the enzymes may also affect phenytoin metabolism and contribute to severe cutaneous adverse reactions," they said.
If these findings are corroborated in future studies, it is possible that patients might be tested for these genetic mutations before they take phenytoin, to prevent these severe and sometimes fatal reactions, the investigators added.
This study was supported by the National Science Council, Taiwan; the National Core Facility Program for Biotechnology, Taiwan; and Chang Gung Memorial Hospital, also in Taiwan. Dr. Chung and a coauthor reported having a patent pending for risk assessment of phenytoin-induced adverse reactions.