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

Aims To examine the potency of ticlopidine (TCL) as an inhibitor of cytochr ome P450s (CYP450s) in vitro using human liver microsomes (HLMs) and recomb inant human CYP450s. Methods Isoform-specific substrate probes of CYP1A2, 2C19, 2C9, 2D6, 2E1 an d 3A4 were incubated in HLMs or recombinant CYPs with or without TCL. Preli minary data were generated to simulate an appropriate range of substrate an d inhibitor concentrations to construct Dixon plots. In order to estimate a ccurately inhibition constants (K-i values) of TCL and determine the type o f inhibition, data from experiments with three different HLMs for each isof orm were fitted to relevant nonlinear regression enzyme inhibition models b y WinNonlin. Results TCL was a potent, competitive inhibitor of CYP2C19 (K-i = 1.2 +/- 0 .5 mu m) and of CYP2D6 (K-i = 3.4 +/- 0.3 mu m). These K-i values fell with in the therapeutic steady-state plasma concentrations of TCL (1-3 mu m). TC L was also a moderate inhibitor of CYP1A2 (K-i = 49 +/- 19 mu m) and a weak inhibitor of CYP2C9 (K-i > 75 mu m), but its effect on the activities of C YP2E1 (K-i = 584 +/- 48 mu m) and CYP3A (> 1000 mu m) was marginal. Conclusions TCL appears to be a broad-spectrum inhibitor of the CYP isoform s, but clinically significant adverse drug interactions are most likely wit h drugs that are substrates of CYP2C19 or CYP2D6.