Identification of Human Liver Cytochrome P450 Enzymes Involved in the Metabolism of SCH 530348 (Vorapaxar), a Potent Oral Thrombin Protease-Activated Receptor 1 Antagonist

Ghosal, Anima; Lu, Xiaowen; Penner, Natasha; Gao, Lan; Ramanathan, Ragu; Chowdhury, Swapan K.; Kishnani, Narendra S.; Alton, Kevin B.

doi:10.1124/dmd.110.035493

Cited by 50 publications

(41 citation statements)

References 16 publications

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“…CYP2J2 is also highly expressed in tumor tissues and promotes tumor growth and proliferation (Jiang et al, 2005(Jiang et al, , 2009Chen et al, 2011). Several drugs are metabolized by CYP2J2 including astemizole, ebastine, terfenadine, albendazole, amiodarone, and most recently vorapaxar (Matsumoto et al, 2003;Lee et al, 2010;Ghosal et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Identifying a Selective Substrate and Inhibitor Pair for the Evaluation of CYP2J2 Activity

Lee¹,

Jones²,

Katayama³

et al. 2012

Drug Metab Dispos

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ABSTRACT:CYP2J2, an arachidonic acid epoxygenase, is recognized for its role in the first-pass metabolism of astemizole and ebastine. To fully assess the role of CYP2J2 in drug metabolism, a selective substrate and potent specific chemical inhibitor are essential. In this study, we report amiodarone 4-hydoxylation as a specific CYP2J2-catalyzed reaction with no CYP3A4, or other drug-metabolizing enzyme, involvement. Amiodarone 4-hydroxylation enabled the determination of liver relative activity factor and intersystem extrapolation factor for CYP2J2. Amiodarone 4-hydroxylation correlated with astemizole O-demethylation but not with CYP2J2 protein content in a sample of human liver microsomes. To identify a specific CYP2J2 inhibitor, 138 drugs were screened using terfenadine and astemizole as probe substrates with recombinant CYP2J2. Forty-two drugs inhibited CYP2J2 activity by >50% at 30 M, but inhibition was substrate-dependent. Of these, danazol was a potent inhibitor of both hydroxylation of terfenadine (IC 50 ‫؍‬ 77 nM) and O-demethylation of astemizole (K i ‫؍‬ 20 nM), and inhibition was mostly competitive. Danazol inhibited CYP2C9, CYP2C8, and CYP2D6 with IC 50 values of 1.44, 1.95, and 2.74 M, respectively. Amiodarone or astemizole were included in a sevenprobe cocktail for cytochrome P450 (P450) drug-interaction screening potential, and astemizole demonstrated a better profile because it did not appreciably interact with other P450 probes. Thus, danazol, amiodarone, and astemizole will facilitate the ability to determine the metabolic role of CYP2J2 in hepatic and extrahepatic tissues.

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Section: Introductionmentioning

confidence: 99%

Identifying a Selective Substrate and Inhibitor Pair for the Evaluation of CYP2J2 Activity

Lee¹,

Jones²,

Katayama³

et al. 2012

Drug Metab Dispos

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“…In humans, vorapaxar is well tolerated and long lasting, with a terminal plasma half-life of 126-269 h and greater than 90% bioavailability after a single loading dose (33). In contrast to the Phase II clinical trial findings with atopaxar, no abnormalities in liver function have been associated with long-term use of vorapaxar (33,34 (35). Although TRACER failed to reach its primary endpoint (a composite of cardiovascular death, myocardial infarction, stroke, recurrent ischemia, or urgent coronary revascularization), the TRA 2…”

Section: Figurementioning

confidence: 50%

Challenges and Opportunities in Protease-Activated Receptor Drug Development

Hamilton

Trejo

2017

Annu. Rev. Pharmacol. Toxicol.

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Protease-activated receptors (PARs) are a unique class of G protein-coupled receptors (GPCRs) that transduce cellular responses to extracellular proteases. PARs have important functions in the vasculature, inflammation, and cancer and are important drug targets. A unique feature of PARs is their irreversible proteolytic mechanism of activation that results in the generation of a tethered ligand that cannot diffuse away. Despite the fact that GPCRs have proved to be the most successful class of druggable targets, the development of agents that target PARs specifically has been challenging. As a consequence, researchers have taken a remarkable diversity of approaches to develop pharmacological entities that modulate PAR function. Here, we present an overview of the diversity of therapeutic agents that have been developed against PARs. We further discuss PAR biased signaling and the influence of receptor compartmentalization, posttranslational modifications, and dimerization, which are important considerations for drug development.

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“…During chronic administration another metabolite-SCH 2046273-accumulates appreciably [22]. This metabolite is equipotent to the parent compound and has a similar halflife.…”

Section: Pars and Par-1 Inhibitorsmentioning

confidence: 93%

Promises of PAR-1 Inhibition in Acute Coronary Syndrome

2011

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Platelet activation is a key process in the pathogenesis of acute coronary syndromes (ACS). Of the many triggers involved in this process, three are presumed to be critical: thromboxane A(2) (TBXA(2)) via the TBXA(2) receptor, adenosine diphosphate via the P2Y(12) receptor, and thrombin via the protease-activated receptor (PAR)-1. Despite the effective inhibition of the first two pathways with aspirin and an expanding family of P2Y(12) inhibitors, the incidence of recurrent ischemic events remains high after ACS. PAR-1 inhibitors are a novel class of antiplatelet agents that inhibit thrombin-mediated platelet activation. Preclinical data and phase 2 clinical trials in patients with stable and unstable coronary disease support the potential of these compounds to improve clinical outcome. In this review we discuss the rationale for developing this novel class of agents with a focus on the two compounds in most advanced clinical development, vorapaxar (SCH 530348) and atopaxar (E5555).

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Identification of Human Liver Cytochrome P450 Enzymes Involved in the Metabolism of SCH 530348 (Vorapaxar), a Potent Oral Thrombin Protease-Activated Receptor 1 Antagonist

Cited by 50 publications

References 16 publications

Identifying a Selective Substrate and Inhibitor Pair for the Evaluation of CYP2J2 Activity

Identifying a Selective Substrate and Inhibitor Pair for the Evaluation of CYP2J2 Activity

Challenges and Opportunities in Protease-Activated Receptor Drug Development

Promises of PAR-1 Inhibition in Acute Coronary Syndrome

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