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 patients in a preparative regimen for bone marrow transplantation consisting of busulfan and CP. Three of the patients received PHE and the other 3 "control" patients received diazepam (DZP) as anti-epileptic prophylactic treatment. Plasma samples were collected at intervals up to 24 h after CP administration. The plasma concentrations of (R)- and (S)-CP and their respective N-dechloroethylated metabolites, (R)- and (S)-DCE-CP were simultaneously fitted using an enantiospecific 2-compartment pharmacokinetic (PK) model with Bayesian control estimation. DZP had no significant effect on the metabolism of CP and any of its PK parameters. PHE, however, increased significantly the formation of (S)-DCE-CP while having no effect on the formation of (R)-DCE-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. Additionally, 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.