In vitro inhibition of the cytochrome P450 (CYP450) system by the antiplatelet drug ticlopidine: Potent effect on CYP2C19 and CYP2D6

Jae Wook Ko, Zeruesenay Desta, Nadia V. Soukhova, Timothy Tracy, David A. Flockhart

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Aims. To examine the potency of ticlopidine (TCL) as an inhibitor of cytochrome P450s (CYP450s) in vitro using human liver microsomes (HLMs) and recombinant human CYP450s. Methods. Isoform-specific substrate probes of CYP1A2, 2C19, 2C9, 2D6, 2E1 and 3A4 were incubated in HLMs or recombinant CYPs with or without TCL. Preliminary data were generated to simulate an appropriate range of substrate and inhibitor concentrations to construct Dixon plots. In order to estimate accurately inhibition constants (K(i) values) of TCL and determine the type of inhibition, data from experiments with three different HLMs for each isoform were fitted to relevant nonlinear regression enzyme inhibition models by WinNonlin. Results. TCL was a potent, competitive inhibitor of CYP2C19 (K(i) = 1.2 ± 0.5 μM) and of CYP2D6 (K(i) = 3.4 ± 0.3 μM). These K(i) values fell within the therapeutic steady-state plasma concentrations of TCL (1-3 μM). TCL was also a moderate inhibitor of CYP1A2 (K(i) = 49 ± 19 μM) and a weak inhibitor of CYP2C9 (K(i) > 75 μM), but its effect on the activities of CYP2E1 (K(i) = 584 ± 48 μM) and CYP3A (> 1000 μM) was marginal. Conclusions. TCL appears to be a broad-spectrum inhibitor of the CYP isoforms, but clinically significant adverse drug interactions are most likely with drugs that are substrates of CYP2C19 or CYP2D6.

Original languageEnglish (US)
Pages (from-to)343-351
Number of pages9
JournalBritish Journal of Clinical Pharmacology
Issue number4
StatePublished - Apr 20 2000



  • Antiplatelet
  • Cytochrome P450
  • Inhibition
  • Ticlopidine

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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