Mp. Ducharme et al., PHENYTOIN-INDUCED ALTERATION IN THE N-DECHLOROETHYLATION OF IFOSFAMIDE STEREOISOMERS, Cancer chemotherapy and pharmacology, 40(6), 1997, pp. 531-533
Case: A suspected alteration in ifosfamide (IFF) metabolism and pharma
cokinetics was observed in a pediatric patient receiving phenytoin. Me
thods: Sequential plasma samples were obtained and analyzed for the co
ncentrations of the enantiomers of IFF and their N-dechloroethylated m
etabolites (DCE-IFF) using a validated enantio selective gas chromatog
raphic-mass spectrometic method. Results: In the phenytoin-treated pat
ient, the metabolic formation of IFF enantiomers was increased and the
metabolic pattern of the N-dechloroethylation altered from nonphenyto
in-treated patients: (R)-3-DCE IFF much greater than(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 much greater than(R)-2-DCE-IFF (patient). Conclusions: Pr
evious 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 CYP
3A4. In addition, the patient, who was at least partially refractory t
o several other treatments, went into remission after IFF treatment su
ggesting that phenytoin pretreatment might increase IFF therapeutic ef
ficacy.