Phenytoin-induced alteration in the N-dechloroethylation of ifosfamide stereoisomers

A suspected alteration in ifosfamide (IFF) metabolism and pharmacokinetics was observed in a pediatric patient receiving phenytoin. Sequential plasma samples were obtained and analyzed for the concentrations of the enantiomers of IFF and their N-dechloroethylated metabolites (DCE-IFF) using a validated enantioselective gas chromatographic-mass spectrometric method. In the phenytoin-treated patient, the metabolic formation of IFF enantiomers was increased and the metabolic pattern of the N-dechloroethylation altered from non-phenytoin-treated patients: (R)-3-DCE IFF > > (S)-3-DCE-IFF = (S)-2-DCE-IFF > (R)-2-DCE-IFF (control) vs (S)-3-DCE-IFF = (S)-2-DCE-IFF > (R)-3-DCE-IFF > > (R)-2-DCE-IFF (patient). Previous studies have attributed the production of the (S)-2-DCE-IFF and (S)-3-DCE-IFF metabolites to the activity of CYP2B6 and (R)-2-DCE-IFF and (R)-3-DCE-IFF to the activity of CYP3A4. The results suggest that phenytoin induced the activity of CYP2B6 to a greater extent than CYP3A4. In addition, the patient, who was at least partially refractory to several other treatments, went into remission after IFF treatment suggesting that phenytoin pretreatment might increase IFF therapeutic efficacy.