Mephenytoin phenotyping: lack of haematologic effect and timing of urine collections.
Mephenytoin is the prototype substrate for the genetically regulated, polymorphically distributed cytochrome P450, mephenytoin hydroxylase. Mephenytoin is an anticonvulsant which has been associated with leukopenia when used chronically. The haematologic effects of a single dose of oral mephenytoin, as is typically used to determine drug metabolism phenotype for this polymorphism, have not been reported. We administered 100 mg oral racemic mephenytoin to 30 healthy male volunteers and measured complete blood count three times weekly for 23 days. The time dependency of the urinary ratio of S to R mephenytoin in five serial urine samples (0-4, 4-8, 8-16, 16-24 and 24-32 h after the dose) was evaluated. There were no significant decreases from baseline in any subject in leukocyte count, haematocrit or platelet count. Two of the 30 subjects both of Indian extraction, were poor metabolizers of mephenytoin. The S:R ratio decreased with time (p = 0.001). Using the 0-4 h urine, one subject would have been misphenotyped as a poor metabolizer; phenotype assignments were in agreement with each other based on all subsequent urine collections. We conclude that there is no evidence that single dose mephenytoin is associated with haematologic toxicity in healthy male volunteers, and that the 4-8 h post-dose urine is as reliable as the 24-32 h collection for assignment of phenotype.
Relling
M V
MV
Pharmaceutical Division, St Jude Children's Research Hospital, Memphis, TN 38105.
Ayers
D
D
Heideman
R L
RL
D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases; D065731:Cytochrome P-450 CYP2C19; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism*; D006400:Hematocrit; D006801:Humans; D007958:Leukocyte Count / Q000187:drug effects; D008297:Male; D008617:Mephenytoin / Q000378:metabolism* / Q000494:pharmacology / Q000652:urine; D006899:Mixed Function Oxygenases / Q000235:genetics* / Q000378:metabolism*; D010641:Phenotype; D010976:Platelet Count / Q000187:drug effects; D013997:Time Factors
D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D008617:Mephenytoin