Enantioselective induction of cyclophosphamide metabolism by phenytoin

Abstract

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. Chirality 11:569–574, 1999. © 1999 Wiley‐Liss, Inc.

Clinical Pharmacology of Cyclophosphamide and Ifosfamide

“…Drug interactions have also been reported with dexamethasone [163], prednisolone [233], phenobarbitone [234], and phenytoin [169] due to induction of CPA metabolism. Phenytoin induces the N-dechloroethylation of the S-enantiomer of CPA to a greater extent than that of the R-enantiomer [235]. The clinical significance of these drug interactions is unclear.…”

Reversal of Resistance to Oxazaphosphorines

“…For example, dexamethasone [166] and phenytoin [271] increased CPA activation due to induction of CPA metabolism in patients. Phenytoin also induces the Ndechloroethylation of the (S)-and (R)-enantiomers of CPA [272]. Similarly, the metabolism (both activation and dechloroethylation) of IFO in cancer patients was increased by concomitant therapy with inducers of CYP3A4 such as phenytoin [273] and phenobarbital [274].…”

“…In vitro, rat model, clinical study [166,274,278,310] Phenytoin Clinical study [272,273,311] ALDH modulators…”

Determination of cyclophosphamide enantiomers in plasma by LC‐MS/MS: Application to pharmacokinetics in breast cancer and lupus nephritis patients

“…4 Despite the vast number of clinical pharmacokinetic reports on CPA, few studies have investigated the stereo- selectivity in the kinetic disposition and metabolism of CPA. 1,[5][6][7][8][9] It has been suggested that (1)-(R) and (2)-(S)-CPA may differ in their therapeutic and toxic effects, but the clinical consequences of these differences have not been adequately determined. 1 Many chromatography-based analytical techniques have been used to measure CPA as enantiomeric mixture in human plasma, including high-performance liquid chromatography with ultraviolet detection (HPLC-UV), gas chromatography-nitrogen phosphorus detection (GC-NPD), gas chromatography-mass spectrometry (GC-MS), liquid chromatography-mass spectrometry (LC-MS), and thinlayer chromatography (TLC)-photography densitometry.…”