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

Kurokawa, Takaya; Fukami, Tatsuki; Yoshida, Tomohiro; Nakajima, Miki

doi:10.1124/dmd.115.068221

Cited by 32 publications

(18 citation statements)

References 27 publications

(47 reference statements)

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“…The hydrolytic rate of the AADAC-specific substrate phenacetin in DIM was approximately 30 pmol/min/mg protein ( Figure 4 ); the clearance of vicagrel was 20.5 ± 1.3 mL/min/mg protein ( Table 1 ). Dog intestine contains considerable AADAC activity ( Kurokawa et al, 2016 ), and AADAC is the main esterase for vicagrel hydrolysis in dog intestine.…”

Section: Discussionmentioning

confidence: 99%

“…The antiplatelet drug prasugrel also contains an acetyl ester bond in the thiophene ring. Intestinal AADAC and CES2 comediated the hydrolysis of prasugrel to produce a thiolactone metabolite; AADAC contributed approximately 50% to its hydrolysis ( Kurokawa et al, 2016 ). Kurokawa et al (2016) found that even though CES protein was not expressed in dog intestine, AADAC activity was functionally observed in dog intestine.…”

Section: Introductionmentioning

confidence: 99%

“…Intestinal AADAC and CES2 comediated the hydrolysis of prasugrel to produce a thiolactone metabolite; AADAC contributed approximately 50% to its hydrolysis ( Kurokawa et al, 2016 ). Kurokawa et al (2016) found that even though CES protein was not expressed in dog intestine, AADAC activity was functionally observed in dog intestine. Vicagrel contains the same acetyl ester bond in the thiophene ring as prasugrel, which confers the substrate specificity of AADAC ( Fukami et al, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

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Arylacetamide Deacetylase Is Involved in Vicagrel Bioactivation in Humans

2017

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Vicagrel, a structural analog of clopidogrel, is now being developed as a thienopyridine antiplatelet agent in a phase II clinical trial in China. Some studies have shown that vicagrel undergoes complete first-pass metabolism in human intestine, generating the hydrolytic metabolite 2-oxo-clopidogrel via carboxylesterase-2 (CES2) and subsequently the active metabolite H4 via CYP450s. This study aimed to identify hydrolases other than CES2 that are involved in the bioactivation of vicagrel in human intestine. This study is the first to determine that human arylacetamide deacetylase (AADAC) is involved in 2-oxo-clopidogrel production from vicagrel in human intestine. In vitro hydrolytic kinetics were determined in human intestine microsomes and recombinant human CES and AADAC. The calculated contribution of CES2 and AADAC to vicagrel hydrolysis was 44.2 and 53.1% in human intestine, respectively. The AADAC-selective inhibitors vinblastine and eserine effectively inhibited vicagrel hydrolysis in vitro. In addition to CES2, human intestine AADAC was involved in vicagrel hydrolytic activation before it entered systemic circulation. In addition, simvastatin efficiently inhibited the production of both 2-oxo-clopidogrel and active H4; further clinical trials are needed to determine whether the hydrolytic activation of vicagrel is influenced by coadministration with simvastatin. This study deepens the understanding of the bioactivation and metabolism properties of vicagrel in humans, which can help further understand the bioactivation mechanism of vicagrel and the variations in the treatment responses to vicagrel and clopidogrel.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Arylacetamide Deacetylase Is Involved in Vicagrel Bioactivation in Humans

2017

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“…The plasma exposure of sirolimus was approximately nine times greater when sirolimus was coadministered with ketoconazole, an inhibitor of CYP3A4 and P-gp to the healthy subjects (Zimmerman, 2004). In addition to CYP3A4, CES2 and arylacetamide deacetylase (AADAC) are also highly expressed in small intestine and contribute to the hydrolysis of many drugs, including flutamide, phenacetin, and prasugrel (Watanabe et al, 2009(Watanabe et al, , 2010Kurokawa et al, 2016). ALS3 is designed to hydrolyze to Exp3174 by esterase; however, the esterase isozymes contributing to ALS3 hydrolysis in which tissues are still in question.…”

Section: Introductionmentioning

confidence: 99%

Carboxylesterase 2 and Intestine Transporters Contribute to the Low Bioavailability of Allisartan, a Prodrug of Exp3174 for Hypertension Treatment in Humans

Li¹,

Sun²,

Guo³

et al. 2019

Drug Metab Dispos

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Exp3174 is an active metabolite of losartan for the treatment of hypertension. Allisartan (ALS3) is a marketed ester prodrug of Exp3174 to reduce bioavailability variation of losartan in China. However, ALS3 exhibited a lower oral absorption than losartan in humans. In this study, the enzymes and transporters involved in ALS3 and Exp3174 disposition were investigated to clarify the mechanisms. ALS3 underwent extensive hydrolysis to Exp3174 in S9 of Caco-2 cells, human intestine microsomes (HIM), recombinant carboxylesterase (rCES) 1, and rCES2. ALS3 exhibited similar affinity in HIM and rCES2 with K m values of 6.92 and 6.77 mM, respectively, indicating that ALS3 is mainly hydrolyzed to Exp3174 in human intestine by CES2. Transport assays of ALS3 and Exp3174 suggested that ALS3 and Exp3174 are substrates of P-glycoprotein, breast cancer resistance protein, and multidrug resistance protein 2 with poor permeability. Organic anion-transporting polypeptide 2B1 showed higher affinity and clearance toward ALS3 (K m 0.75 mM and intrinsic clearance 215 ml/min/mg) than those of Exp3174 (K m 7.85 mM and intrinsic clearance 16.1 ml/min/mg), indicating that ALS3 is preferred to be uptaken into intestinal epithelia. Hydrolysis of ALS3 was increased from approximately 30% to 55% in CES2-transfected human embryonic kidney 293-OATP2B1 cells, indicating the possible interplay between OATP2B1 and CES2. The influx and efflux of ALS3 across Caco-2 cells increased the potential of ALS3 hydrolysis to Exp3174, and the produced Exp3174 was rapidly pumped out, which led to undetectable ALS3 and Exp3174 in basolateral (receiver) side in Caco-2 cells. Overall, our study provided supportive evidences that the interplay between CES2 and transporters in intestine contributes to the low bioavailability of ALS3 in humans.

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“…AADAC is a single serine esterase expressed in the human liver and intestinal tract and to a lesser extent in the pancreas and adrenal gland (Fukami and Yokoi, 2012;Quiroga and Lehner, 2018;Yoshida et al, 2018). This enzyme is principally involved in the hydrolysis of several drugs containing the acetyl group, such as phenacetin, flutamide, rifamycins, prasugrel, ketoconazole, and indiplon (Watanabe et al, 2009(Watanabe et al, , 2010Nakajima et al, 2011;Shimizu et al, 2014a,b;Fukami et al, 2016;Kurokawa et al, 2016). In a previous study, Watanabe et al (2010) demonstrated that AADAC is the principal enzyme involved in phenacetin hydrolysis with respect to CES enzyme contribution.…”

Section: Introductionmentioning

confidence: 99%

Arylacetamide Deacetylase Enzyme: Presence and Interindividual Variability in Human Lungs

et al. 2019

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Human arylacetamide deacetylase (AADAC) is a single microsomal serine esterase involved in the hydrolysis of many acetyl-containing drugs. To date, the presence and activity of the AADAC enzyme in human lungs has been scarcely examined. We investigated its gene and protein expression as well as interindividual variations in AADAC activities in a large number of human lungs (n 5 25) using phenacetin as a selective substrate. The kinetic parameters K m and V max were determined. Our findings highlighted a high interindividual variability in both AADAC mRNA levels and hydrolysis activities. Furthermore, for the first time we demonstrated the presence of the AADAC protein in various lung samples by means of immunoblot analysis. As a comparison, phenacetin hydrolysis was detected in pooled human liver microsomes. Lung activities were much lower than those found in the liver. However, similar K m values were found, which suggests that this hydrolysis could be due to the same enzyme. Pulmonary phenacetin hydrolysis proved to be positively correlated with AADAC mRNA (*P < 0.05) and protein (*P < 0.05) levels. Moreover, the average values of AADAC activity in smokers was significantly higher than in nonsmoker subjects (*P < 0.05), and this might have an important role in the administration of some drugs. These findings add more information to our knowledge of pulmonary enzymes and could be particularly useful in the design and preclinical development of inhaled drugs. SIGNIFICANCE STATEMENT This study investigated the presence and activity of the AADAC enzyme in several human lungs. Our results highlight high interindividual variability in both AADAC gene and protein expression as well as in phenacetin hydrolysis activity. These findings add more information to our knowledge of pulmonary enzymes and could be particularly useful in the design and preclinical development of inhaled drugs.

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

Cited by 32 publications

References 27 publications

Arylacetamide Deacetylase Is Involved in Vicagrel Bioactivation in Humans

Arylacetamide Deacetylase Is Involved in Vicagrel Bioactivation in Humans

Carboxylesterase 2 and Intestine Transporters Contribute to the Low Bioavailability of Allisartan, a Prodrug of Exp3174 for Hypertension Treatment in Humans

Arylacetamide Deacetylase Enzyme: Presence and Interindividual Variability in Human Lungs

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