title: Excretion of the principal urinary metabolites of phenytoin and absolute oral bioavailability determined by use of a stable isotope in patients with epilepsy.
abstract: BACKGROUND
  The anticonvulsant properties of phenytoin (PHT) were discovered in 1938. Since then, it has been one of the most widely used antiepileptic drugs. It is slowly absorbed, extensively plasma protein-bound, exhibits a nonlinear, concentration-dependent pharmacokinetic profile, and has a narrow therapeutic range.
  
  
  METHODS
  We determined PHT bioavailability during steady-state therapy by 1) measurement of the two principal deconjugated PHT urinary metabolites, 5-(4-hydroxyphenyl)-5-phenylhydantoin (p-HPPH) and 5-(3,4-dihydroxy-1,5-cyclohexadien-1-yl)-5-phenylhydantoin (DHD); and 2) direct determination of absolute bioavailability after simultaneous administration of an oral formulation and parenteral stable-labeled PHT (SL-PHT). Urinary metabolites were quantified by an isocratic HPLC-NI-APCI-MS method. The urinary dose recovery was calculated by dividing the molar recovery of the major PHT urinary metabolites by the molar dose received.
  
  
  RESULTS
  Urinary metabolite recovery was surprisingly low, 35.4% ± 15.7% in younger patients (age 21-49 years old) and 32.9% ± 15.0% in patients aged 65 to 93 years. Absolute bioavailability was 86.4% ± 19.4% and 92.5% ± 25.2%, respectively. A weak, but significant, Spearman rank correlation was observed between urinary metabolite recovery and oral bioavailability (P = 0.00924, R = 0.166).
  
  
  CONCLUSIONS
  This weak correlation may be the result of variability in urinary versus biliary-fecal excretion of p-HPPH glucuronide. This study demonstrates that daily PHT oral absorption exhibits wide interpatient variability, which may account for fluctuations in PHT concentration over time.
authors.affiliation: Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Theresa
authors.initials: T
authors.lastname: Aliwarga
authors.forename: James C
authors.initials: JC
authors.lastname: Cloyd
authors.forename: Varun
authors.initials: V
authors.lastname: Goel
authors.forename: Richard C
authors.initials: RC
authors.lastname: Brundage
authors.forename: Susan E
authors.initials: SE
authors.lastname: Marino
authors.forename: Ilo E
authors.initials: IE
authors.lastname: Leppik
authors.forename: Rory P
authors.initials: RP
authors.lastname: Remmel
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000927:Anticonvulsants / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use / Q000652:urine*; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D016903:Drug Monitoring; D004827:Epilepsy / Q000188:drug therapy; D005260:Female; D006801:Humans; D007553:Isotope Labeling; D008297:Male; D008875:Middle Aged; D010672:Phenytoin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use / Q000652:urine; D055815:Young Adult
chemical_list: D000927:Anticonvulsants; C027363:5-(3,4-dihydroxy-1,5-cyclohexadien-1-yl)-5-phenylhydantoin; C030590:5-phenyl-5-(4-hydroxyphenyl)hydantoin glucuronide; D010672:Phenytoin