Ticlopidine inhibition of phenytoin metabolism mediated by potent inhibition of CYP2C19

Stephen K. Donahue, David A. Flockhart, Darrell R. Abernethy, Jae Wook Ko

Research output: Contribution to journalArticle

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Abstract

A patient who had taken a stable dose of phenytoin for 2 years had a coronary stent placed for unstable angina and ticlopidine was added to this therapeutic regimen. Twenty-five days later, he was hospitalized with acute symptomatic phenytoin toxicity and a serum concentration of 46.5% μg/ml. Determination of metabolic genotype revealed that the patient had a wild-type genotype for CYP2C9, CYP2C19, and CYP2D6. Using human liver microsomes, we showed that ticlopidine is a potent inhibitor of cytochrome P450 2C19, with an estimated inhibition constant (K(i)) of 3.7 ± 0.2 μmol/L. The influence of ticlopidine on CYP2C9, the other cytochrome P450 isoform that metabolizes phenytoin, is relatively weak, with a calculated K(i) of 38.8 ± 27 μmol/L. These data suggest that, in this patient, phenytoin toxicity was caused by inhibition of CYP2C19 by ticlopidine, and the data emphasize the importance of CYP2C19 in the metabolism of phenytoin.

Original languageEnglish (US)
Pages (from-to)572-577
Number of pages6
JournalClinical Pharmacology and Therapeutics
Volume62
Issue number5
DOIs
StatePublished - Nov 1997
Externally publishedYes

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Ticlopidine
Phenytoin
Cytochrome P-450 Enzyme System
Genotype
Cytochrome P-450 CYP2D6
Unstable Angina
Liver Microsomes
Stents
Protein Isoforms
Cytochrome P-450 CYP2C19
Inhibition (Psychology)
Serum

ASJC Scopus subject areas

  • Pharmacology

Cite this

Ticlopidine inhibition of phenytoin metabolism mediated by potent inhibition of CYP2C19. / Donahue, Stephen K.; Flockhart, David A.; Abernethy, Darrell R.; Ko, Jae Wook.

In: Clinical Pharmacology and Therapeutics, Vol. 62, No. 5, 11.1997, p. 572-577.

Research output: Contribution to journalArticle

Donahue, Stephen K. ; Flockhart, David A. ; Abernethy, Darrell R. ; Ko, Jae Wook. / Ticlopidine inhibition of phenytoin metabolism mediated by potent inhibition of CYP2C19. In: Clinical Pharmacology and Therapeutics. 1997 ; Vol. 62, No. 5. pp. 572-577.
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