Enantioselective induction of cyclophosphamide metabolism by phenytoin

The objective of this study was to investigate the effect of phenytoin (PHE ) on cyclophosphamide (CP) disposition. CP was administered to 6 adult pati ents in a preparative regimen for bone marrow transplantation consisting of busulfan and CP. Three of the patients received PHE and the other 3 "contr ol" patients received diazepam (DZP) as anti-epileptic prophylactic treatme nt. Plasma samples were collected at intervals up to 24 h after CP administ ration. The plasma concentrations of (R)- and Q-CP and their respective N-d echloroethylated metabolites, (R)- and (S)-DCE-CP were simultaneously fitte d using an enantiospecific 2-compartment pharmacokinetic (PK) model with Ba yesian control estimation. DZP had no significant effect on the metabolism of CP and any of its PK parameters. PHE, however, increased significantly t he formation of (S) DCE-CP while having no effect on the formation of (R)-D CE-CP. These results suggest that different enzymes are responsible for the formation of (S)-DCE-CP from (S)-CP and (R)-DCE-CP from (R)-CP. Additional ly, assuming that PHE does not affect the passive renal elimination of (R)- and (S)-CP, this analysis suggests that the clearance of both (R)-and (S)- CP to 4-hydroxy-CP (the activation pathway) is increased by PHE. (C) 1999 W iley-Liss, Inc.