The Biotransformation of Prasugrel, a New Thienopyridine Prodrug, by the Human Carboxylesterases 1 and 2

Williams, Eric T.; Jones, Karen O.; Ponsler, G. Douglas; Lowery, Shane M.; Perkins, E.J.; Wrighton, Steven; Ruterbories, Kenneth J.; Kazui, Miho; Farid, Nagy A.

doi:10.1124/dmd.107.020248

Cited by 119 publications

(97 citation statements)

References 24 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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“…Prasugrel hydrolysis was reported to be mainly catalyzed by CES2 in human intestine (Williams et al, 2008). To investigate whether CES2 is the sole enzyme involved in this hydrolysis, we performed kinetic analyses of prasugrel hydrolase activity using recombinant human AADAC, CES1, and CES2.…”

Section: Resultsmentioning

confidence: 99%

“…Prasugrel is efficiently hydrolyzed to prasugrel thiolactone in the intestine after oral administration, followed by oxidation to an active metabolite by CYP3A4 and CYP2B6 in the intestine and liver (Rehmel et al, 2006;Farid et al, 2007;Williams et al, 2008). It has been believed that prasugrel hydrolysis was catalyzed by CES2 in humans (Williams et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

“…It is a prodrug that is activated by hydrolysis and hydroxylation in the body. Previous reports have demonstrated that after oral administration to humans, prasugrel is efficiently hydrolyzed to prasugrel thiolactone by carboxylesterase (CES)2 in the intestine, followed by oxidization to an active metabolite by cytochrome P450 (CYP)3A4 and CYP2B6 in the intestine and liver (Rehmel et al, 2006;Farid et al, 2007;Williams et al, 2008) (Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

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Arylacetamide Deacetylase is Responsible for Activation of Prasugrel in Human and Dog

Kurokawa

Fukami

Yoshida

et al. 2015

Drug Metabolism and Disposition

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Prasugrel, a thienopyridine anti-platelet agent, is pharmacologically activated by hydrolysis and hydroxylation. It is efficiently hydrolyzed in the intestine after oral administration, and the enzyme responsible for the hydrolysis in humans was demonstrated to be carboxylesterase (CES)2. Prasugrel hydrolase activity is detected in dog intestines, where CES enzymes are absent; therefore, this prompted us to investigate the involvement of an enzyme(s) other than CES. Human arylacetamide deacetylase (AADAC) is highly expressed in the small intestine, catalyzing the hydrolysis of several clinical drugs containing small acyl moieties. In the present study, we investigated whether AADAC catalyzes prasugrel hydrolysis. Recombinant human AADAC was shown to catalyze prasugrel hydrolysis with a CL int value of 50.0 6 1.2 ml/min/mg protein with a similar K m value to human intestinal and liver microsomes, whereas the CL int values of human CES1 and CES2 were 4.6 6 0.1 and 6.6 6 0.3 ml/min/mg protein, respectively. Inhibition studies using various chemical inhibitors and the relative activity factor approach suggested that the contribution of AADAC to prasugrel hydrolysis in human intestine is comparable to that of CES2. In dog intestine, the expression of AADAC, but not CES1 and CES2, was confirmed by measuring the marker hydrolase activities of each human esterase. The similar K m values and inhibition profiles between recombinant dog AADAC and small intestinal microsomes suggest that AADAC is a major enzyme responsible for prasugrel hydrolysis in dog intestine. Collectively, we found that AADAC largely contributes to prasugrel hydrolysis in both human and dog intestine.

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“…Празугрел сильнее подавляет актив-ность тромбоцитов, начинает действовать за более ОРИГИНАЛЬНЫЕ СТАТЬИ и CYP2B6, и в меньшей степени -CYP2C9 и CYP2C19 [23]. Возможные механизмы резистентности к празуг-релу: плохая приверженность к терапии, нарушение абсорбции, лекарственные взаимодействия (совмест-ное применение ингибиторов CYP3A4), недостаточ-ная доза препарата, полиморфизмы P2Y12 рецепто-ров [24].…”

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Antiplatelet Therapy in Prophilaxy of Negative Cardiovascular Events After Coronary Revascularization. Is There a Consensus?

Косинова¹,

Гринштейн²

2014

Russ J Cardiol

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The Biotransformation of Prasugrel, a New Thienopyridine Prodrug, by the Human Carboxylesterases 1 and 2

Cited by 119 publications

References 24 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

Arylacetamide Deacetylase is Responsible for Activation of Prasugrel in Human and Dog

Antiplatelet Therapy in Prophilaxy of Negative Cardiovascular Events After Coronary Revascularization. Is There a Consensus?

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