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Enantioselective metabolism of ifosfamide by the kidney

Katarina Aleksa1, Shinya Ito, Gideon Koren

  • 1Division of Clinical Pharmacology and Toxicology, Hospital for Sick Children, Toronto, Canada.

Chirality
|April 1, 2006
PubMed

Insights

Ifosfamide (IF) metabolism in the kidney is enantioselective, with the (S)-enantiomer producing more toxic metabolites. Using (R)-IF may reduce kidney damage from this chemotherapy drug.

Area of Science:

  • Pharmacology
  • Nephrology
  • Drug Metabolism

Background:

  • Ifosfamide (IF) is a chemotherapy drug used for solid tumors.
  • IF causes significant nephrotoxicity, likely due to renal chloroacetaldehyde production.
  • Enantioselective metabolism of IF has been observed in the liver but not previously in the kidney.

Purpose of the Study:

  • To investigate the enantioselectivity of Ifosfamide (IF) metabolism in kidney tissues.
  • To determine if specific IF enantiomers are preferentially metabolized in the kidney.
  • To explore the potential of using enantiomerically pure IF to reduce nephrotoxicity.

Main Methods:

  • Utilized porcine and human kidney samples for metabolic studies.
  • Employed the renal porcine cell line LLCPK-1 for in vitro analysis.
  • Quantified N-dechloroethylifosfamide (DCEIF) metabolites produced from (R)-IF and (S)-IF enantiomers.

Main Results:

  • Demonstrated enantioselective metabolism of IF in both porcine and human kidney samples.
  • Observed significantly higher production of DCEIF metabolites from the (S)-IF enantiomer compared to the (R)-IF enantiomer.
  • Confirmed these findings using the LLCPK-1 renal cell line.

Conclusions:

  • Kidney metabolism of Ifosfamide (IF) is enantioselective.
  • The (S)-IF enantiomer is preferentially metabolized, potentially leading to increased nephrotoxicity.
  • Replacing racemic IF with (R)-IF could mitigate IF-induced kidney damage, as both enantiomers have similar efficacy.

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