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Enantioselective induction of cyclophosphamide metabolism by phenytoin
Author(s) -
Williams Marion L.,
Wainer Irving W.,
Embree Leanne,
Barnett Michael,
Granvil Camille L.,
Ducharme Murray P.
Publication year - 1999
Publication title -
chirality
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.43
H-Index - 77
eISSN - 1520-636X
pISSN - 0899-0042
DOI - 10.1002/(sici)1520-636x(1999)11:7<569::aid-chir9>3.0.co;2-r
Subject(s) - chemistry , pharmacokinetics , phenytoin , cyclophosphamide , pharmacology , busulfan , metabolism , diazepam , stereochemistry , medicine , epilepsy , biochemistry , chemotherapy , neuroscience , biology
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.