Falsely increased immunoassay measurements of total and unbound phenytoin in critically III uremic patients receiving fosphenytoin

Background: Fosphenytoin, a phosphate ester prodrug of phenytoin, is metabolized to phenytoin in vivo. Phenytoin metabolites accumulate in renal insufficiency and cross-react in some phenytoin immunoassays. Our aim was to determine the accuracy of phenytoin immunoassays in renal patients treated with fosphenytoin. Methods: We measured phenytoin with HPLC and with the aca, ACS:180, TDx phenytoin II, Vitros, and AxSYM methods. Specimens were collected 2-120 h after fosphenytoin administration from 17 patients with renal insufficiency. Results: The AxSYM, TDx phenytoin II, ACS:180, and Vitros assays displayed falsely increased phenytoin results up to 20 times higher than the HPLC results. The aca Star results for these specimens were comparable to the HPLC results. Although fosphenytoin can cross-react with phenytoin immunoassays, no fosphenytoin was detected by a sensitive HPLC method in any sample that was tested for its presence. Conclusion: These results are consistent with the formation of one or more novel metabolites or adducts of fosphenytoin that accumulate in some critically ill patients with renal insufficiency and that display significant cross-reactivity with some, but not all, phenytoin immunoassay methods.