Comparison of Human Cytochrome P450 Inhibition by the Thienopyridines Prasugrel, Clopidogrel, and Ticlopidine

Hagihara, Katsunobu; Nishiya, Yoshiaki; Kurihara, Atsushi; Kazui, Miho; Farid, Nagy A.; Ikeda, Toshihiko

doi:10.2133/dmpk.23.412

Cited by 69 publications

(54 citation statements)

References 29 publications

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“…For both clopidogrel and ticlopidine, the first step in the formation of the thiolactone is an oxidative step in which reactive intermediates are likely to be formed, as evidenced by their mechanism-based inhibitory effects on the activities of CYP2B6 and CYP2C19 (Ha-Duong et al, 2001;Nishiya et al, 2009a,b). However, prasugrel is converted to the thiolactone by hydrolysis in the intestine during the absorption process through the action of carboxylesterases (Williams et al, 2008), and the key prasugrel metabolites are not mechanism-based inhibitors (Rehmel et al, 2006;Hagihara et al, 2008;Nishiya et al, 2009a,b). The active metabolite of clopidogrel is thought to be formed primarily in the liver (Savi et al, 1992;Farid et al, 2010), whereas the active metabolite of prasugrel is thought to be partly formed by intestinal CYP3A before the thiolactone reaches the liver (Farid et al, , 2010.…”

Section: Discussionmentioning

confidence: 99%

Biotransformation of Prasugrel, a Novel Thienopyridine Antiplatelet Agent, to the Pharmacologically Active Metabolite

Hagihara

Kazui²,

Kurihara³

et al. 2010

Drug Metab Dispos

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ABSTRACT:Prasugrel, a novel thienopyridine antiplatelet agent, undergoes rapid hydrolysis in vivo to a thiolactone, R-95913, which is further converted to its thiol-containing, pharmacologically active metabolite, R-138727, by oxidation via cytochromes P450 (P450). We trapped a sulfenic acid metabolite as a mixed disulfide with 2-nitro-5-thiobenzoic acid in an incubation mixture containing the thiolactone R-95913, expressed CYP3A4, and NADPH. Further experiments investigated one possible mechanism for the conversion of the sulfenic acid to the active thiol metabolite in vitro. A mixed disulfide form of R-138727 with glutathione was found to be a possible precursor of R-138727 in vitro when glutathione was present. The rate constant for the reduction of the glutathione conjugate of R-138727 to R-138727 was increased by addition of human liver cytosol to the human liver microsomes. Thus, one possible mechanism for the ultimate formation of R-138727 in vitro can be through formation of a sulfenic acid mediated by P450s followed possibly by a glutathione conjugation to a mixed disulfide and reduction of the disulfide to the active metabolite R-138727. Prasugrel [Effient (Eli Lilly and Company, Indianapolis, IN) in the United States and Efient (Eli Lilly and Company) in the EuropeanUnion], clopidogrel [Plavix (Sanofi-Aventis, Paris, France)/Iscover (Bristol-Myers Squibb, New York, NY)], and ticlopidine (Ticlid; Sanofi-Aventis) are thienopyridine antiplatelet agents. Prasugrel has been shown to reduce the rate of thrombotic cardiovascular events and stent thrombosis in patients with acute coronary syndrome that are undergoing percutaneous coronary intervention (Wiviott et al., 2007) (Effient package insert). The thienopyridines are prodrugs that are converted in vivo to their pharmacologically active metabolites that possess a thiol group via a corresponding thiolactone metabolite (Farid et al., 2010). However, with the exception of an oxidation step catalyzed by cytochrome P450 (Savi et al., 1994;Rehmel et al., 2006), the mechanism for the active metabolite formation from thienopyridines remained unknown until recently reported for ticlopidine and clopidogrel (Dansette et al., 2009). In the case of prasugrel, the active metabolite R-138727 was not detected when the thiolactone metabolite R-95913 was incubated with liver homogenates or microsomes in the absence of cofactors, but it was detected when NADPH and a reducing agent such as glutathione were added to the system (Kazui et al., 2000). A sulfenic acid, which is a likely intermediate for the activation of prasugrel, reacts readily with a thiol compound, typically glutathione in vivo, to yield a disulfide metabolite (Decker et al., 1991;Kassahun et al., 2001;Reddy et al., 2005;Dansette et al., 2009). The formed disulfide can be further reduced to provide a thiolcontaining compound. The objective of this study is to investigate the involvement of a sulfenic acid and a glutathione conjugate of R-138727 in the in vitro production of prasugrel's active metabolite (R-1...

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Section: Discussionmentioning

confidence: 99%

Biotransformation of Prasugrel, a Novel Thienopyridine Antiplatelet Agent, to the Pharmacologically Active Metabolite

Hagihara

Kazui²,

Kurihara³

et al. 2010

Drug Metab Dispos

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“…Because clopidogrel acid metabolite showed high stability in human liver microsomes and weaker inhibitory effects on P450s compared with clopidogrel and the thiolactone metabolite of clopidogrel (Hagihara et al, 2008), it is unlikely that clopidogrel acid metabolite exhibits mechanism-based inhibition of CYP2B6.…”

Section: Discussionmentioning

confidence: 99%

“…Because of the P450 dependency of the metabolic pathways, ticlopidine, clopidogrel, and the thiolactone metabolites of ticlopidine, clopidogrel, and prasugrel could have the potential to cause a drug-drug interaction through the inhibition of P450s. Indeed, several in vitro studies indicated that ticlopidine, clopidogrel, and their thiolactone metabolites are competitive inhibitors of several P450s (Ko et al, 2000;Turpeinen et al, 2004;Hagihara et al, 2008). R-95913 was shown not to be an inhibitor of CYP1A2, CYP3A, CYP2C9, CYP2C19, and CYP2D6 at clinical doses (K i values ranged from 7.2 to 82 M) (Rehmel et al, 2006).…”

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confidence: 99%

“…Because the pharmacologically active metabolites of thienopyridine antiplatelet agents have a thiol group that has been assumed to irreversibly bind to the target P2Y 12 receptor on platelets through a disulfide bond formation (Ding et al, 2003), Richter et al (2004) suggested that a possible mechanism for the irreversible inactivation of CYP2B6 by ticlopidine and clopidogrel would be the binding of the active metabolites to the P450 protein. Hagihara et al (2008) reported that the active, thiol-containing metabolites themselves do not inhibit CYP2B6. Thus, the possibility was raised that either clopidogrel and ticlopidine and/or their thiolactone metabolites produced by CYP2B6 may be involved in the mechanism-based inhibition.…”

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confidence: 99%

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Mechanism-Based Inhibition of Human Cytochrome P450 2B6 by Ticlopidine, Clopidogrel, and the Thiolactone Metabolite of Prasugrel

Nishiya

Hagihara²,

Ito³

et al. 2008

Drug Metab Dispos

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ABSTRACT:Mechanism-based inhibition of CYP2B6 in human liver microsomes by thienopyridine antiplatelet agents ticlopidine and clopidogrel and the thiolactone metabolites of those two agents plus that of prasugrel were investigated by determining the time-and concentration-dependent inhibition of the activity of bupropion hydroxylase as the typical CYP2B6 activity. By comparing the ratios of k inact (maximal inactivation rate constant)/K I (the inactivator concentration producing a half-maximal rate of inactivation), it was found that the thiolactone metabolite of prasugrel is 10-and 22-fold less potent, respectively, in the mechanism-based inhibition of CYP2B6 than ticlopidine and clopidogrel. The k inact /K I ratio of the thiolactone metabolite of ticlopidine was comparable with that of the parent compound, whereas this ratio for the thiolactone metabolite of clopidogrel was significantly smaller than that of clopidogrel. In conclusion, ticlopidine, its thiolactone metabolite, and clopidogrel were more potent mechanism-based inhibitors of CYP2B6 than the thiolactone metabolite of prasugrel.The thienopyridine antiplatelet agents ticlopidine and clopidogrel ( Fig. 1) prevent thrombogenesis via blocking ADP-dependent activation of platelets through the P2Y 12 receptor, one of the ADP receptors on platelets (Sharis et al., 1998). They have been widely used for the treatment and prevention of cerebrovascular and cardiovascular diseases. Clopidogrel appears to have a relatively faster onset of action and lower incidence of adverse effects such as neutropenia and thrombotic thrombocytopenic purpura compared with ticlopidine (Kam and Nethery, 2003).Prasugrel ( Fig. 1), a novel thienopyridine P2Y 12 antagonist, demonstrated more potent antiplatelet activity and faster onset than ticlopidine and clopidogrel in preclinical and/or clinical studies (Niitsu et al., 2005;Brandt et al., 2007) and efficacy superior to that of clopidogrel in patients with acute coronary syndrome undergoing percutaneous coronary intervention . Prasugrel, also a prodrug, is first hydrolyzed to a thiolactone metabolite (R-95913), which is then converted to the pharmacologically active metabolite (R-138727) through a single, P450-mediated oxidation step (Fig. 1) (Rehmel et al., 2006;Williams et al., 2008).The thiolactone metabolites of ticlopidine and clopidogrel are produced by P450-mediated oxidation (Yoneda et al., 2004;Kurihara et al., 2005), whereas R-95913 is produced by esterase-mediated hydrolysis of prasugrel (Williams et al., 2008). The hydrolysis of prasugrel is very rapid both in vitro and in vivo, such that it is not detected in human plasma even at early time points after oral administration . The thiolactones of each of these agents are converted to the pharmacologically active metabolites, each of which possesses a thiol group, by P450-mediated oxidation (Yoneda et al., 2004;Kurihara et al., 2005;Rehmel et al., 2006). Because of the P450 dependency of the metabolic pathways, ticlopidine, clopidogrel, and the thiolactone metabolites o...

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“…However, there is no clinical evidence for the pharmacokinetic interaction of clopidogrel with cerivastatin, and a study of any drug-drug interaction (DDI) between clopidogrel and cerivastatin is problematic because cerivastatin is not available as a drug for clinical study. Moreover, clopidogrel and its metabolites inhibit not only CYP-mediated metabolism (CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP3A4) but also OATP1B1 in vitro, and their in vitro inhibition constants (K i ) values were considered to affect the pharmacokinetic interactions of coadministered drugs (Hagihara et al, 2008;Nishiya et al, 2009a,b;Tamraz et al, 2013;Tornio et al, 2014). The effects of clopidogrel on the pharmacokinetics of CYP2B6 substrates and CYP2C19 substrates clearly include that the plasma concentrations of efavirenz, omeprazole, and sibutramine are increased by a mechanism-based inhibition of CYP2B6, CYP2C19, and both, respectively (Chen et al, 2009;Bae et al, 2011;Jiang et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Clarification of the Mechanism of Clopidogrel-Mediated Drug-Drug Interaction in a Clinical Cassette Small-dose Study and Its Prediction Based on In Vitro Information

Kim

Yoshikado

Ieiri

et al. 2016

Drug Metabolism and Disposition

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Clopidogrel is reported to be associated with cerivastatin-induced rhabdomyolysis, and clopidogrel and its metabolites are capable of inhibiting CYP2C8 and OATP 1B1 in vitro. The objective of the present study was to identify the mechanism of clopidogrelmediated drug-drug interactions (DDIs) on the pharmacokinetics of OATP1B1 and/or CYP2C8 substrates in vivo. A clinical cassette small-dose study using OATPs, CYP2C8, and OATP1B1/CYP2C8 probe drugs (pitavastatin, pioglitazone, and repaglinide, respectively) with or without the coadministration of either 600 mg rifampicin (an inhibitor for OATPs), 200 mg trimethoprim (an inhibitor for CYP2C8), or 300 mg clopidogrel was performed, and the area under the concentration-time curve (AUC) ratios (AUCRs) for probe substrates were predicted using a static model. Clopidogrel increased the AUC of pioglitazone (2.0-fold) and repaglinide (3.1-fold) but did not significantly change the AUC of pitavastatin (1.1-fold). In addition, the AUC of pioglitazone M4, a CYP2C8-mediated metabolite of pioglitazone, was reduced to 70% of the control by coadministration of clopidogrel. The predicted AUCRs using the mechanism-based inhibition of CYP2C8 by clopidogrel acyl-b-glucuronide were similar to the observed AUCRs, and the predicted AUCR (1.1) of repaglinide using only the inhibition of OATP1B1 did not reach the observed AUCR (3.1). In conclusion, a single 300 mg of clopidogrel mainly inhibits CYP2C8-mediated metabolism by clopidogrel acylb-glucuronide, but its effect on the pharmacokinetics of OATP1B1 substrates is negligible. Clopidogrel is expected to have an effect not only on CYP2C8 substrates, but also dual CYP2C8/OATP1B1 substrates as seen in the case of repaglinide.

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Comparison of Human Cytochrome P450 Inhibition by the Thienopyridines Prasugrel, Clopidogrel, and Ticlopidine

Cited by 69 publications

References 29 publications

Biotransformation of Prasugrel, a Novel Thienopyridine Antiplatelet Agent, to the Pharmacologically Active Metabolite

Biotransformation of Prasugrel, a Novel Thienopyridine Antiplatelet Agent, to the Pharmacologically Active Metabolite

Mechanism-Based Inhibition of Human Cytochrome P450 2B6 by Ticlopidine, Clopidogrel, and the Thiolactone Metabolite of Prasugrel

Clarification of the Mechanism of Clopidogrel-Mediated Drug-Drug Interaction in a Clinical Cassette Small-dose Study and Its Prediction Based on In Vitro Information

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