TY - JOUR T1 - Role of CYP2B6 and CYP3A4 in the In Vitro<em>N</em>-Dechloroethylation of (<em>R</em>)- and (<em>S</em>)-Ifosfamide in Human Liver Microsomes JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 533 LP - 541 VL - 27 IS - 4 AU - Camille P. Granvil AU - Ajay Madan AU - Mahmoud Sharkawi AU - Andrew Parkinson AU - Irving W. Wainer Y1 - 1999/04/01 UR - http://dmd.aspetjournals.org/content/27/4/533.abstract N2 - The central nervous system toxicity of ifosfamide (IFF), a chiral antineoplastic agent, is thought to be dependent on itsN-dechloroethylation by hepatic cytochrome P-450 (CYP) enzymes. The purpose of this study was to identify the human CYPs responsible for IFF-N-dechloroethylation and their corresponding regio- and enantioselectivities. IFF exists in two enantiomeric forms, (R) - and (S)-IFF, which can be dechloroethylated at either the N2 or N3 positions, producing the corresponding (R,S)-2-dechloroethyl-IFF [(R,S)-2-DCE-IFF] and (R,S)-3-dechloroethyl-IFF [(R,S)-3-DCE-IFF]. The results of the present study suggest that the production of (R)-2-DCE-IFF and (S)-3-DCE-IFF from (R)-IFF is catalyzed by different CYPs as is the production of (S)-2-DCE-IFF and (R)-3-DCE-IFF from (S)-IFF. In vitro studies with a bank of human liver microsomes revealed that the sample-to-sample variation in the production of (S)-3-DCE-IFF from (R)-IFF and (S)-2-DCE-IFF from (S)-IFF was highly correlated with the levels of (S)-mephenytoinN-demethylation (CYP2B6), whereas (R)-2-DCE-IFF production from (R)-IFF and (R)-3-DCE-IFF production from (S)-IFF were both correlated with the activity of testosterone 6β-hydroxylation (CYP3A4/5). Experiments with cDNA-expressed P-450 and antibody and chemical inhibition studies supported the conclusion that the formation of (S)-3-DCE-IFF and (S)-2-DCE-IFF is catalyzed primarily by CYP2B6, whereas (R)-2-DCE-IFF and (R)-3-DCE-IFF are primarily the result of CYP3A4/5 activity. The American Society for Pharmacology and Experimental Therapeutics ER -