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|stevens - johnson syndrome||0|
|Ki: ||Kd:||Ic 50:||Ec50/Ic50:|
In vitro inhibition of the cytochrome P450 (CYP450) system by the antiplatelet drug ticlopidine: potent effect on CYP2C19 and CYP2D6.. J W Ko; Z Desta; N V Soukhova; T Tracy; D A Flockhart (2000) British journal of clinical pharmacology display 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 (Ki 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 (Ki = 1.2 +/- 0.5 microM) and of CYP2D6 (Ki = 3.4 +/- 0.3 microM). These Ki values fell within the therapeutic steady-state plasma concentrations of TCL (1-3 microM). TCL was also a moderate inhibitor of CYP1A2 (Ki = 49 +/- 19 microM) and a weak inhibitor of CYP2C9 (Ki > 75 microM), but its effect on the activities of CYP2E1 (Ki = 584 +/- 48 microM) and CYP3A (> 1000 microM) 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.
Potent mechanism-based inhibition of human CYP2B6 by clopidogrel and ticlopidine.. Tanja Richter; Thomas E Mürdter; Georg Heinkele; Jürgen Pleiss; Stephan Tatzel; Matthias Schwab; Michel Eichelbaum; Ulrich M Zanger (2004) The Journal of pharmacology and experimental therapeutics display abstract
The thienopyridine derivatives ticlopidine and clopidogrel are inhibitors of ADP-induced platelet aggregation. Pharmacological activity of these prodrugs depends on cytochrome P450 (P450)-dependent oxidation to the active antithrombotic agent. In this study, we investigated the interaction potential of clopidogrel and ticlopidine by using human liver microsomes and recombinantly expressed P450 isoforms. Both clopidogrel and ticlopidine inhibited CYP2B6 with highest potency and CYP2C19 with lower potency. Clopidogrel also inhibited CYP2C9, and ticlopidine also inhibited CYP1A2, with lower potency. Inhibition of CYP2B6 was time- and concentration-dependent, and as shown by dialysis experiments, it was irreversible and dependent on NADPH, suggesting a mechanism-based mode of action. Inactivation was of nonpseudo-firstorder type with maximal rates of inactivation (K(inact)) for clopidogrel and ticlopidine in microsomes (recombinant CYP2B6) of 0.35 (1.5 min(-1)) and 0.5 min(-1) (0.8 min(-1)), respectively, and half-maximal inactivator concentrations (KI) were 0.5 microM (1.1 microM) for clopidogrel and 0.2 microM (0.8 microM) for ticlopidine. Inhibition was attenuated by the presence of alternative active site ligands but not by nucleophilic trapping agents or reactive oxygen scavengers, further supporting mechanism-based action. A chemical mechanism is discussed based on the known metabolic activation of clopidogrel and on the finding that hemoprotein integrity of recombinant CYP2B6 was not affected by irreversible inhibition. These results suggest the possibility of drug interactions between thienopyridine derivates and drug substrates of CYP2B6 and CYP2C19.