Detection and quantification of (R) and (S)-dechloroethylifosfamide metabolites in plasma from children by enantioselective LC/MS/MS.
Ifosfamide (IF), a potent chemotherapeutic agent for solid tumors, is known to cause high rates of nephrotoxicity in children with cancer, which is most likely due to the renal production of the metabolite chloroacetaldehyde. Using plasma samples obtained from pediatric oncology patients, we developed a simple nonderivatizing enantioselective liquid chromatography mass spectrometry method to detect the (R) and (S)-2- and 3-dechloroethylifosfamide metabolites. The (R) and (S)-enantiomers of the 2- and 3-DCEIF (N-3-dechlroethylifosfamide) were detectable in all 22 patients' samples with levels ranging from 9.9 to 238.7 ng/ml for (R)-2-DCEIF, 15.8 to 663.0 ng/ml for (S)-2-DCEIF, 20.8 to 852.8 ng/l for (R)-3-DCEIF and 28.0 to 862.0 ng/ml for (S)-3-DCEIF. In addition, the lower limit of quantification for this method is 1 ng/ml. Future studies should concentrate on (R) or (S) production of the 2-DCEIF and 3-DCEIF and subsequently chloroacetaldehyde formation with the aim of considering the administration of only the (R)-IF as its metabolism results in a lower production of chloroacetaldehyde.
Aleksa
Katarina
K
Division of Clinical Pharmacology and Toxicology, Hospital for Sick Children, Toronto, Canada.
Nava-Ocampo
Alejandro
A
Koren
Gideon
G
D000079:Acetaldehyde / Q000031:analogs & derivatives / Q000737:chemistry; D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D002853:Chromatography, Liquid; D003520:Cyclophosphamide / Q000031:analogs & derivatives* / Q000032:analysis; D006801:Humans; D007069:Ifosfamide / Q000031:analogs & derivatives* / Q000032:analysis / Q000378:metabolism*; D007223:Infant; D013058:Mass Spectrometry / Q000379:methods; D010372:Pediatrics; D010950:Plasma Cells / Q000737:chemistry; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods; D013237:Stereoisomerism
C064445:dechloroethylcyclophosphamide; D003520:Cyclophosphamide; C004656:chloroacetaldehyde; D000079:Acetaldehyde; C038007:dechloroethylifosfamide; D007069:Ifosfamide