Diphenylhydantoic acid (
DPHA) is a degradation product in parenteral formulations of the
anticonvulsant phenytoin and the
prodrug fosphenytoin.
DPHA has also been reported to be a minor metabolite of
phenytoin. Levels found in the urine of various species, including humans, after oral or intravenous (iv)
phenytoin ranged from undetected to a few percent of administered dose. In the present analysis, the toxicologic profile of
DPHA was integrated with exposure data in order to characterize its safety under recommended clinical regimens of
fosphenytoin administration. In preclinical safety studies,
DPHA was without effect in the Ames assay and at concentrations up to 3000 microg/plate in the presence or absence of metabolic activation, and in the in vitro micronucleus test with acute and 2-week repeated dose studies in Wistar rats at iv doses up to 15 mg/kg. In 4-week studies conducted in rats and dogs receiving
fosphenytoin containing
DPHA levels up to 1.1%, and in an in vitro structural
chromosome aberration test with
DPHA levels up to 2.0%, all findings were consistent with known effects of
phenytoin (such as CNS signs and increased liver weight), and none were attributed to
DPHA. Reports in the literature indicate that in murine in vivo and in vitro models,
DPHA has much lower potential for reproductive toxicity than
phenytoin. A no-observed-effect level (NOEL) of 15 mg/kg established from the 2-week study in rats was used with probabilistic techniques to estimate tolerable daily doses (TDDs) of
DPHA. In this approach, interspecies correction was performed by allometrically scaling the NOEL based on a distributional power of
body weight while intraindividual variability was accounted for by selecting the lower percentiles of the population-based distribution of TDDs. The results indicate that a
DPHA content limit of 3.0% in an administered dose of
fosphenytoin is unlikely to cause adverse effects in patients.