Enantioselective metabolism of ifosfamide by the kidney.
Ifosfamide (IF), a potent chemotherapeutic agent for solid tumors, is known to cause high rates of nephrotoxicity, which is most likely due to the renal production of the metabolite chloroacetaldehyde. Enantioselective oxidation of IF has been shown in the liver but has never been reported in the kidney. Using porcine and human kidney samples, as well as the renal porcine cell line LLCPK-1, we document enantioselective metabolism of IF with prevalent production of the N-dechloroethylifosfamide (DCEIF) metabolites from the (S)-IF enantiomer compared to the amount of N-DCEIF metabolites produced from the (R)-IF enantiomers. Since IF enantiomers appear to be equally effective in chemotherapy, these results suggest that replacing the clinically standard racemic mixture of IF with (R)-IF may decrease renal metabolism of the drug and hence may decrease nephrotoxicity.
Division of Clinical Pharmacology and Toxicology, Hospital for Sick Children, Toronto, Canada.
Katarina
K
Aleksa
Shinya
S
Ito
Gideon
G
Koren
D000293:Adolescent; D000328:Adult; D017677:Age Distribution; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000502:physiology*; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000032:analysis / Q000737:chemistry / Q000378:metabolism*; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D007069:Ifosfamide / Q000032:analysis / Q000737:chemistry / Q000378:metabolism*; D007223:Infant; D007668:Kidney / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000378:metabolism; D008297:Male; D008861:Microsomes / Q000378:metabolism; D008862:Microsomes, Liver / Q000378:metabolism; D008875:Middle Aged; D015394:Molecular Structure; D013237:Stereoisomerism; D034421:Sus scrofa; D013997:Time Factors
D018906:Antineoplastic Agents, Alkylating; D007069:Ifosfamide