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In vitro inhibition of the cytochrome P450 (CYP450) system by the antiplatelet drug ticlopidine: potent effect on CYP2C19 and CYP2D6
Author(s) -
Ko, Jae Wook,
Desta, Zeruesenay,
Soukhova, Nadia V,
Tracy Timothy,
Flockhart David A
Publication year - 2000
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1046/j.1365-2125.2000.00175.x
Subject(s) - cyp1a2 , cyp2d6 , pharmacology , cyp2c9 , cytochrome p450 , microsome , chemistry , non competitive inhibition , cyp2e1 , cyp3a4 , cyp2c19 , cyp3a , protease inhibitor (pharmacology) , cyp2c8 , in vitro , biochemistry , enzyme , biology , human immunodeficiency virus (hiv) , antiretroviral therapy , viral load , immunology
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 µ m ) and of CYP2D6 ( K i = 3.4 ± 0.3 µ m ). These K i values fell within the therapeutic steady‐state plasma concentrations of TCL (1–3 µ m ). TCL was also a moderate inhibitor of CYP1A2 ( K i = 49 ± 19 µ m ) and a weak inhibitor of CYP2C9 ( K i > 75 µ m ), but its effect on the activities of CYP2E1 ( K i = 584 ± 48 µ m ) and CYP3A (> 1000 µ m ) 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.