title: Pharmacokinetic model analysis of interaction between phenytoin and capecitabine.
abstract: OBJECTIVE
  Recent reports have shbown an increase in serum phenytoin levels resulting in phenytoin toxicity after initiation of luoropyrimidine chemotherapy. To prevent phenytoin intoxication, phenytoin dosage must be adjusted. We sought to develop a pharmacokinetic model of the interaction between phenytoin and capecitabine.
  
  
  METHODS
  We developed the phenytoin-capecitabine interaction model on the assumption that fluorouracil (5-FU) inhibits cytochrome P450 (CYP) 2C9 synthesis in a concentration- dependent manner. The plasma 5-FU concentration after oral administration of capecitabine was estimated using a conventional compartment model. Nonlinear pharmacokinetics of phenytoin was modeled by incorporating the Michaelis-Menten equation to represent the saturation of phenytoin metabolism. The resulting model was fitted to data from our previously-reported cases.
  
  
  RESULTS
  The developed phenytoincapecitabine interaction model successfully described the profiles of serum phenytoin concentration in patients who received phenytoin and capecitabine concomitantly. The 50% inhibitory 5-FU concentration for CYP2C9 synthesis and the degradation rate constant of CYP2C9 were estimated to be 0.00310 ng/mL and 0.0768 day-1, respectively. This model and these parameters allow us to predict the appropriate phenytoin dosage schedule when capecitabine is administered concomitantly.
  
  
  CONCLUSIONS
  This newly-developed model accurately describes changes in phenytoin concentration during concomitant capecitabine chemotherapy, and it may be clinically useful for predicting appropriate phenytoin dosage adjustments for maintaining serum phenytoin levels within the therapeutic range.
authors.forename: Shohei
authors.initials: S
authors.lastname: Miyazaki
authors.forename: Hiroki
authors.initials: H
authors.lastname: Satoh
authors.forename: Masayuki
authors.initials: M
authors.lastname: Ikenishi
authors.forename: Miyuki
authors.initials: M
authors.lastname: Sakurai
authors.forename: Mutsuaki
authors.initials: M
authors.lastname: Ueda
authors.forename: Kaori
authors.initials: K
authors.lastname: Kawahara
authors.forename: Rie
authors.initials: R
authors.lastname: Ueda
authors.forename: Tohru
authors.initials: T
authors.lastname: Ohtori
authors.forename: Kenji
authors.initials: K
authors.lastname: Matsuyama
authors.forename: Akiko
authors.initials: A
authors.lastname: Miki
authors.forename: Satoko
authors.initials: S
authors.lastname: Hori
authors.forename: Eiji
authors.initials: E
authors.lastname: Fukui
authors.forename: Eitaro
authors.initials: E
authors.lastname: Nakatsuka
authors.forename: Yasufumi
authors.initials: Y
authors.lastname: Sawada
mesh_terms: D000284:Administration, Oral; D000927:Anticonvulsants / Q000008:administration & dosage / Q000493:pharmacokinetics; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000494:pharmacology; D000069287:Capecitabine / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D065729:Cytochrome P-450 CYP2C9 / Q000187:drug effects / Q000378:metabolism; D004347:Drug Interactions; D005472:Fluorouracil / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D008954:Models, Biological; D017711:Nonlinear Dynamics; D010672:Phenytoin / Q000008:administration & dosage / Q000493:pharmacokinetics*
chemical_list: D000927:Anticonvulsants; D000964:Antimetabolites, Antineoplastic; D010672:Phenytoin; D000069287:Capecitabine; D065729:Cytochrome P-450 CYP2C9; D005472:Fluorouracil