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

Research output: Contribution to journalArticle

92 Citations (Scopus)

Abstract

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
Volume49
Issue number4
DOIs
StatePublished - 2000
Externally publishedYes

Fingerprint

Ticlopidine
Cytochrome P-450 CYP2D6
Platelet Aggregation Inhibitors
Cytochrome P-450 Enzyme System
Liver Microsomes
Protein Isoforms
Cytochromes
Cytochrome P-450 CYP3A
Cytochrome P-450 CYP2E1
Cytochrome P-450 CYP1A2
In Vitro Techniques
Cytochrome P-450 CYP2C19
Drug Interactions
Enzymes
Pharmaceutical Preparations

Keywords

  • Antiplatelet
  • Cytochrome P450
  • Inhibition
  • Ticlopidine

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology, Toxicology and Pharmaceutics(all)

Cite this

In vitro inhibition of the cytochrome P450 (CYP450) system by the antiplatelet drug ticlopidine : Potent effect on CYP2C19 and CYP2D6. / Ko, Jae Wook; Desta, Zeruesenay; Soukhova, Nadia V.; Tracy, Timothy; Flockhart, David A.

In: British Journal of Clinical Pharmacology, Vol. 49, No. 4, 2000, p. 343-351.

Research output: Contribution to journalArticle

@article{8f46c497852147399a7f7f2658c71d74,
title = "In vitro inhibition of the cytochrome P450 (CYP450) system by the antiplatelet drug ticlopidine: Potent effect on CYP2C19 and CYP2D6",
abstract = "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.",
keywords = "Antiplatelet, Cytochrome P450, Inhibition, Ticlopidine",
author = "Ko, {Jae Wook} and Zeruesenay Desta and Soukhova, {Nadia V.} and Timothy Tracy and Flockhart, {David A.}",
year = "2000",
doi = "10.1046/j.1365-2125.2000.00175.x",
language = "English (US)",
volume = "49",
pages = "343--351",
journal = "British Journal of Clinical Pharmacology",
issn = "0306-5251",
publisher = "Wiley-Blackwell",
number = "4",

}

TY - JOUR

T1 - In vitro inhibition of the cytochrome P450 (CYP450) system by the antiplatelet drug ticlopidine

T2 - Potent effect on CYP2C19 and CYP2D6

AU - Ko, Jae Wook

AU - Desta, Zeruesenay

AU - Soukhova, Nadia V.

AU - Tracy, Timothy

AU - Flockhart, David A.

PY - 2000

Y1 - 2000

N2 - 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.

AB - 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.

KW - Antiplatelet

KW - Cytochrome P450

KW - Inhibition

KW - Ticlopidine

UR - http://www.scopus.com/inward/record.url?scp=0034128040&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0034128040&partnerID=8YFLogxK

U2 - 10.1046/j.1365-2125.2000.00175.x

DO - 10.1046/j.1365-2125.2000.00175.x

M3 - Article

C2 - 10759690

AN - SCOPUS:0034128040

VL - 49

SP - 343

EP - 351

JO - British Journal of Clinical Pharmacology

JF - British Journal of Clinical Pharmacology

SN - 0306-5251

IS - 4

ER -