Hydroxylation and N-dechloroethylation of Ifosfamide and deuterated Ifosfamide by the human cytochrome p450s and their commonly occurring polymorphisms.
The hydroxylation and N-dechloroethylation of deuterated ifosfamide (d4IFO) and ifosfamide (IFO) by several human P450s have been determined and compared. d4IFO was synthesized with deuterium at the alpha and alpha' carbons to decrease the rate of N-dechloroethylation and thereby enhance hydroxylation of the drug at the 4' position. The purpose was to decrease the toxic and increase the efficacious metabolites of IFO. For all of the P450s tested, hydroxylation of d4IFO was improved and dechloroethylation was reduced as compared with nondeuterated IFO. Although the differences were not statistically significant, the trend favoring the 4'-hydroxylation pathway was noteworthy. CYP3A5 and CYP2C19 were the most efficient enzymes for catalyzing IFO hydroxylation. The importance of these enzymes in IFO metabolism has not been reported previously and warrants further investigation. The catalytic ability of the common polymorphisms of CYP2B6 and CYP2C9 for both reactions were tested with IFO and d4IFO. It was determined that the commonly expressed polymorphisms CYP2B6*4 and CYP2B6*6 had reduced catalytic ability for IFO compared with CYP2B6*1, whereas CYP2B6*7 and CYP2B6*9 had enhanced catalytic ability. As with the wild-type enzymes, d4IFO was more readily hydroxylated by the polymorphic variants than IFO, and d4IFO was not dechloroethylated by any of the polymorphic forms. We also assessed the use of specific inhibitors of P450 to favor hydroxylation in human liver microsomes. We were unable to separate the pathways with these experiments, suggesting that multiple P450s are responsible for catalyzing both metabolic pathways for IFO, which is not observed with the closely related drug cyclophosphamide.
Department of Pharmacology, University of Michigan, Ann Arbor, Michigan (D.M.C., H.Z., P.F.H.); Department of Basic and Social Sciences, Albany College of Pharmacy and Health Sciences, Albany, New York (S.L.); and Department of Medicine, University of Chicago, Chicago, Illinois (M.E.D.).
Diane M
DM
Calinski
Department of Pharmacology, University of Michigan, Ann Arbor, Michigan (D.M.C., H.Z., P.F.H.); Department of Basic and Social Sciences, Albany College of Pharmacy and Health Sciences, Albany, New York (S.L.); and Department of Medicine, University of Chicago, Chicago, Illinois (M.E.D.).
Haoming
H
Zhang
Department of Pharmacology, University of Michigan, Ann Arbor, Michigan (D.M.C., H.Z., P.F.H.); Department of Basic and Social Sciences, Albany College of Pharmacy and Health Sciences, Albany, New York (S.L.); and Department of Medicine, University of Chicago, Chicago, Illinois (M.E.D.).
Susan
S
Ludeman
Department of Pharmacology, University of Michigan, Ann Arbor, Michigan (D.M.C., H.Z., P.F.H.); Department of Basic and Social Sciences, Albany College of Pharmacy and Health Sciences, Albany, New York (S.L.); and Department of Medicine, University of Chicago, Chicago, Illinois (M.E.D.).
M Eileen
ME
Dolan
Department of Pharmacology, University of Michigan, Ann Arbor, Michigan (D.M.C., H.Z., P.F.H.); Department of Basic and Social Sciences, Albany College of Pharmacy and Health Sciences, Albany, New York (S.L.); and Department of Medicine, University of Chicago, Chicago, Illinois (M.E.D.) phollen@umich.edu.
Paul F
PF
Hollenberg
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000378:metabolism* / Q000493:pharmacokinetics*; D002384:Catalysis; D065702:Cytochrome P-450 CYP2B6 / Q000235:genetics / Q000378:metabolism; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics / Q000378:metabolism; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism*; D003903:Deuterium; D006801:Humans; D006900:Hydroxylation; D007069:Ifosfamide / Q000378:metabolism* / Q000493:pharmacokinetics*; D066298:In Vitro Techniques; D007553:Isotope Labeling; D008862:Microsomes, Liver / Q000378:metabolism; D011110:Polymorphism, Genetic / Q000235:genetics; D051381:Rats
D018906:Antineoplastic Agents, Alkylating; D003577:Cytochrome P-450 Enzyme System; D003903:Deuterium; D065729:Cytochrome P-450 CYP2C9; D065702:Cytochrome P-450 CYP2B6; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; D007069:Ifosfamide