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

Background: Fosphenytoin, a phosphate ester prodrug of phenytoin, is metabo lized to phenytoin in vivo. Phenytoin metabolites accumulate in renal insuf ficiency and cross-react in some phenytoin immunoassays. Our aim was to det ermine the accuracy of phenytoin immunoassays in renal patients treated wit h fosphenytoin. Methods: We measured phenytoin with HPLC and with the aca, ACS:180, TDx phe nytoin II, Vitros, and AxSYM methods. Specimens were collected 2-120 h afte r 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 res ults. The aca Star results for these specimens were comparable to the HPLC results. Although fosphenytoin can crossreact 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 critic ally ill patients with renal insufficiency and that display significant cro ss-reactivity with some, but not all, phenytoin immunoassay methods. (C) 19 99 American Association for Clinical Chemistry.