Stereoselectivity in metabolism of ifosfamide by CYP3A4 and CYP2B6

Abstract

The aim was to identify the hepatic cytochromes P450 (CYPs) responsible for the enantioselective metabolism of ifosfamide (IFA). The 4-hydroxylation, N2- and N3-dechloroethylation of IFA enantiomers were monitored simultaneously in the same metabolic systems using GC/MS and pseudoracemate techniques. In human and rat liver microsomes, (R)-IFA was preferentially metabolized via 4-hydroxylation, whereas its antipode was biotransformed in favour of N-dechloroethylation. CYP3A4 was the major enzyme responsible for metabolism of IFA enantiomers in human liver. The study also revealed that CYP3A (human CYP3A4/5 and rat CYP3A1/2) and CYP2B (human CYP2B6 and rat CYP2B1/2) enantioselectively mediated the 4-hydroxylation, N2- and N3-dechloroethylation of IFA. CYP3A preferentially supported the formation of (R)-4-hydroxyIFA (HOIF), (R)-N2-dechloroethylIFA (N2D) and (R)-N3-dechloroethylIFA (N3D), whereas CYP2B preferentially mediated the generation of (S)-HOIF, (S)-N2D and (S)-N3D. The enantioselective metabolism of IFA by CYP3A4 and CYP2B1 was confirmed in cDNA transfected V79 cells.

Common Polymorphisms of CYP2B6 Influence Stereoselective Bupropion Disposition

“…In contrast, metabolism of racemic bupropion is less by both CYP2B6.4 and CYP2B6.6, as is racemic ifosfamide, which is metabolized more efficiently by CYP2B6.7 and CYP2B6.9 . Ifosfamide metabolism by CYP2B6.1 is enantioselective, but stereoselectivity with CYP2B6 variants is unknown. Cyclophosphamide hydroxylation by CYP2B6.6 was greater than CYP2B6.1 in vitro , but this was not apparent clinically .…”

Stage Dependent Enantioselective Metabolism of Bifenthrin in Embryos of Zebrafish (Danio rerio) and Japanese Medaka (Oryzias latipes)

“…KCZ also exhibited greater inhibition of 1 S - cis -BF metabolism. Stereoselectivity has primarily been observed in several CYP2 orthologs in mammals with CYP2C19 having been identified as one of the most stereoselective. , As KCZ also selectively inhibits CYP2C19, an orthologous form in zebrafish may similarly catalyze BF hydroxylation. Additional studies with purified or “knocked out” CYPs may help identify the enzymes responsible for the 4-hydroxylation of BF.…”

Multidisciplinary Insights into the Structure–Function Relationship of the CYP2B6 Active Site

“…CYP2B6 and CYP3A4 also tend to differ in their enantioselectivity as seen with ifosfamide since the former preferentially metabolizes (S)-ifosfamide while the latter prefers (R)ifosfamide (Roy et al, 1999;Niwa et al, 2011). Some have attributed this observation to the potential for an enantiomeric/mirror arrangement of the CYP2B6 and CYP3A4 active sites (Lu et al, 2006). (S)-Methadone has a lower Km for N-demethylation by CYP2B6 which is also the principal metabolizer of racemic methadone (Gerber et al, 2004;Crettol et al, 2005;Totah et al, 2008).…”