Interaction magnitude, pharmacokinetics and pharmacodynamics of ticlopidine in relation to CYP2C19 genotypic status

Ichiro Ieiri, Miyuki Kimura, Shin Irie, Akinori Urae, Kenji Otsubo, Takashi Ishizaki

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Objectives: 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.

Original languageEnglish
Pages (from-to)851-859
Number of pages9
JournalPharmacogenetics and Genomics
Volume15
Issue number12
DOIs
Publication statusPublished - Jan 1 2005
Externally publishedYes

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Ticlopidine
Pharmacokinetics
Omeprazole
Platelet Aggregation
Cytochrome P-450 CYP2C19
Adenosine Diphosphate
Area Under Curve

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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Interaction magnitude, pharmacokinetics and pharmacodynamics of ticlopidine in relation to CYP2C19 genotypic status. / Ieiri, Ichiro; Kimura, Miyuki; Irie, Shin; Urae, Akinori; Otsubo, Kenji; Ishizaki, Takashi.

In: Pharmacogenetics and Genomics, Vol. 15, No. 12, 01.01.2005, p. 851-859.

Research output: Contribution to journalArticle

Ieiri, Ichiro ; Kimura, Miyuki ; Irie, Shin ; Urae, Akinori ; Otsubo, Kenji ; Ishizaki, Takashi. / Interaction magnitude, pharmacokinetics and pharmacodynamics of ticlopidine in relation to CYP2C19 genotypic status. In: Pharmacogenetics and Genomics. 2005 ; Vol. 15, No. 12. pp. 851-859.
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T1 - Interaction magnitude, pharmacokinetics and pharmacodynamics of ticlopidine in relation to CYP2C19 genotypic status

AU - Ieiri, Ichiro

AU - Kimura, Miyuki

AU - Irie, Shin

AU - Urae, Akinori

AU - Otsubo, Kenji

AU - Ishizaki, Takashi

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N2 - Objectives: 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.

AB - Objectives: 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.

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