title: Interaction magnitude, pharmacokinetics and pharmacodynamics of ticlopidine in relation to CYP2C19 genotypic status.
abstract: OBJECTIVE
  The aim of this study was to investigate the impact of CYP2C19 polymorphism on the extent of the interaction and on the pharmacokinetics and pharmacodynamics of ticlopidine.
  
  
  METHODS
  Homozygous (hmEMs) and heterozygous extensive metabolizers (htEMs), and poor metabolizers (PMs, n = 6 each) took an oral dose (20 mg) of omeprazole. After a 1-week washout period, each subject received ticlopidine (200 mg) for 8 days, and ticlopidine pharmacokinetics were studied on days 1 and 7. On day 8, omeprazole was given again and its kinetic disposition was compared with that in the first dose. ADP-induced platelet aggregation was measured as a pharmacodynamic index.
  
  
  RESULTS
  In contrast to the PMs, whose mean kinetic parameters were not altered by the repeated dosings of ticlopidine, an eight- to 10-fold increase in the mean AUC ratio of omeprazole to 5-hydroxyomeprazole was observed in both the EM groups. No significant intergenotypic differences in the pharmacokinetic parameters of ticlopidine were observed, although the accumulation ratio tended to be greater in hmEMs than in PMs (2.4 +/- 0.2 versus 1.7 +/- 0.2). A significantly positive correlation (P = 0.031) was observed between the individual percent inhibition of platelet aggregation and AUC0-24 of ticlopidine regardless of the CYP2C19 polymorphism.
  
  
  CONCLUSIONS
  Ticlopidine is a potent inhibitor for CYP2C19 and may be associated with the phenocopy when CYPC19 substrates are co-administered to EMs. Whether and to what extent CYP2C19 would be involved in the metabolism of ticlopidine remain unanswered from the present in-vivo study.
authors.affiliation: Department of Hospital Pharmacy, Faculty of Medicine, Tottori University, Yonago, Japan. ieieei-ttr@umin.ac.jp
authors.forename: Ichiro
authors.initials: I
authors.lastname: Ieiri
authors.forename: Miyuki
authors.initials: M
authors.lastname: Kimura
authors.forename: Shin
authors.initials: S
authors.lastname: Irie
authors.forename: Akinori
authors.initials: A
authors.lastname: Urae
authors.forename: Kenji
authors.initials: K
authors.lastname: Otsubo
authors.forename: Takashi
authors.initials: T
authors.lastname: Ishizaki
mesh_terms: D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism*; D065731:Cytochrome P-450 CYP2C19; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D005838:Genotype; D006801:Humans; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D009853:Omeprazole / Q000031:analogs & derivatives / Q000494:pharmacology; D013988:Ticlopidine / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D009853:Omeprazole; D013988:Ticlopidine