Urinary excretion of phenytoin metabolites, 5-(4'-hydroxyphenyl)-5-phenylhydantoin and its O-glucuronide in humans and analysis of genetic polymorphisms of UDP-glucuronosyltransferases

Drug Metab Pharmacokinet. 2005 Apr;20(2):135-43. doi: 10.2133/dmpk.20.135.

Abstract

The anticonvulsant agent phenytoin (5,5-diphenylhydantoin) is mainly excreted as 5-(4'-hydroxyphenyl)-5-phenylhydantoin (4'-HPPH) O-glucuronide in humans. Previously, we demonstrated that the glucuronidation of 4'-HPPH is catalyzed by multiple UDP-glucuronosyltransferases (UGTs) of UGT1A1, UGT1A4, UGT1A6, and UGT1A9. Since 4'-HPPH may be bioactivated to a reactive metabolite by peroxidase, the glucuronidation in considered to be a detoxification pathway. In the present study, we investigated the relationship between the extent of interindividual variability in the urinary excretion levels of 4'-HPPH and its O-glucuronide and genotyping of CYP2C9, CYP2C19, UGT1A1, UGT1A6, and UGT1A9. 4'-HPPH and its glucuronide in urine samples from 15 patients to whom phenytoin was administered were measured by liquid chromatography-tandem mass spectrometry. When the molar ratio of 4'-HPPH O-glucuronide/4'-HPPH was calculated as an index of glucuronidation, a large interindividual variability (11 fold) was observed in the 15 patients. Phenytoin is metabolized to 4'-HPPH by CYP2C9 and CYP2C19 in which there are genetic polymorphisms. Although 5 patients were genotyped as heterozygotes of mutated alleles of CYP2C9 or CYP2C19 genes, no relationship with the interindividual difference in the total excretion levels of 4'-HPPH and its O-glucuronide was observed. The UGT1A1*6, UGT1A1*28, UGT1A1*60 and UGT1A6*2 alleles were found in 1, 3, 6, and 8 patients, respectively. Although there was no relationship between the genetic polymorphisms of UGT1As and the interindividual difference in the 4'-HPPH glucuronidation, the large interindividual variability of 4'- HPPH glucuronidation may contribute to interindividual differences in toxic reactions to phenytoin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Anticonvulsants / pharmacokinetics
  • Female
  • Glucuronosyltransferase / genetics
  • Glucuronosyltransferase / metabolism*
  • Humans
  • Male
  • Middle Aged
  • Phenytoin / analogs & derivatives*
  • Phenytoin / pharmacokinetics
  • Phenytoin / urine*
  • Polymorphism, Genetic

Substances

  • Anticonvulsants
  • hydroxyphenytoin
  • 5-phenyl-5-(4-hydroxyphenyl)hydantoin glucuronide
  • Phenytoin
  • Glucuronosyltransferase