Screening of Specific Inhibitors for Human Carboxylesterases or Arylacetamide Deacetylase

Shimizu, Mai; Fukami, Tatsuki; Nakajima, Miki; Yokoi, Tsuyoshi

doi:10.1124/dmd.114.056994

Cited by 83 publications

(74 citation statements)

References 37 publications

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“…If no metabolism is observed in the recombinant CES, the probability of CES involvement is low and no further evaluation is warranted. If NME metabolism is observed in the recombinant CES system, further assessment can be conducted using subcellular fractions, e.g., human liver (CES1 enriched, low CES2 levels) and intestinal (CES2 only) microsomal and/or S9 systems, in combination with specific substrates and inhibitors listed in Tables 2-5, to evaluate the relative contribution of CES to overall clearance (Zhu et al, 2009;Ross et al, 2012;Nishimuta et al, 2014;Shimizu et al, 2014). There are no known CESmediated metabolic DDIs reported, making this enzyme class as a potentially low risk for causing metabolic DDIs.…”

Section: Determining Relative Role Of Carboxylesterase Ces1 and Ces2mentioning

confidence: 99%

Evaluation of a New Molecular Entity as a Victim of Metabolic Drug-Drug Interactions--an Industry Perspective

Bohnert¹,

Patel²,

Templeton³

et al. 2016

Drug Metabolism and Disposition

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Under the guidance of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ), scientists from 20 pharmaceutical companies formed a Victim Drug-Drug Interactions Working Group. This working group has conducted a review of the literature and the practices of each company on the approaches to clearance pathway identification (f CL ), estimation of fractional contribution of metabolizing enzyme toward metabolism (f m ), along with modeling and simulation-aided strategy in predicting the victim drug-drug interaction (DDI) liability due to modulation of drug metabolizing enzymes. Presented in this perspective are the recommendations from this working group on: 1) strategic and experimental approaches to identify f CL and f m , 2) whether those assessments may be quantitative for certain enzymes (e.g., cytochrome P450, P450, and limited uridine diphosphoglucuronosyltransferase, UGT enzymes) or qualitative (for most of other drug metabolism enzymes), and the impact due to the lack of quantitative information on the latter. Multiple decision trees are presented with stepwise approaches to identify specific enzymes that are involved in the metabolism of a given drug and to aid the prediction and risk assessment of drug as a victim in DDI. Modeling and simulation approaches are also discussed to better predict DDI risk in humans. Variability and parameter sensitivity analysis were emphasized when applying modeling and simulation to capture the differences within the population used and to characterize the parameters that have the most influence on the prediction outcome.

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Section: Determining Relative Role Of Carboxylesterase Ces1 and Ces2mentioning

confidence: 99%

Evaluation of a New Molecular Entity as a Victim of Metabolic Drug-Drug Interactions--an Industry Perspective

Bohnert¹,

Patel²,

Templeton³

et al. 2016

Drug Metabolism and Disposition

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“…In a recent study, the inhibitory potencies of 542 compounds against human AADAC using a recombinant enzyme was investigated, and it was found that several compounds or drugs, such as benzbromarone and vinblastine, potently inhibited AADAC activity (Shimizu et al, 2014b). However, there are no clinical reports for drug-drug interaction in which the involvement of AADAC is suspected, probably because such a combination would be rare in clinical studies.…”

Section: Discussionmentioning

confidence: 99%

“…of triplicate determinations. (Watanabe et al, 2009;Shimizu et al, 2014b). Eserine potently inhibits CES2 and AADAC at 10 mM (Kobayashi et al, 2012a).…”

Section: Methodsmentioning

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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“…It is likely as the same enzyme metabolises both ethyl and methylphenidate that ethylphenidate would also be affected [30], and that concomitant administration of a drug such as heroin (which is also metabolised by hCES1a [30]) and other potent inhibitors of carboxylesterase such as ethanol, digitonin, telmisartan [36], aripiprazole, fluoxetine [37] and loperamide [38] could also cause increases in the blood levels of ethylphenidate if taken concomitantly, potentially to fatal levels.…”

Section: Resultsmentioning

confidence: 99%

Seven fatalities associated with ethylphenidate

Maskell

Smith

Cole

et al. 2016

Forensic Science International

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Ethylphenidate is a stimulant novel psychoactive substance that is an analogue of the prescription drug methylphenidate (Ritalin ®. Methylphenidate is used commonly for the treatment of attention deficit hyperactivity disorder. Due to its stimulant effects ethylphenidate is being abused. There is a single case report of a death associated with ethylphenidate in Germany, and a case series of 19 deaths in the East of Scotland, but otherwise, the contribution of ethylphenidate to death is poorly documented. We report the analytical results of 7 cases (between February 2013 and January 2015) in which ethylphenidate was detected and quantitated with a validated liquid chromatography tandem mass spectrometry method (LC-MS/MS). The individuals (all male) ranged in age from 23 to 49 years (median 25 years). The concentration of ethylphenidate in the cases ranged from 0.026 mg/L to 2.18 mg/L in unpreserved post-mortem femoral blood. Only one case had ethylphenidate present as a sole drug. All other cases had at least 2 other drug classes present (benzodiazepines, heroin, methadone antipsychotics, other new psychoactive compounds). Ethylphenidate toxicity was the sole contribution to the cause of death in one case. Hanging was the cause of death in 2 cases, with the other 4 cases being reported as having occurred due to mixed drug toxicity. These data will further help with the interpretation of post-mortem ethylphenidate levels.

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Screening of Specific Inhibitors for Human Carboxylesterases or Arylacetamide Deacetylase

Cited by 83 publications

References 37 publications

Evaluation of a New Molecular Entity as a Victim of Metabolic Drug-Drug Interactions--an Industry Perspective

Evaluation of a New Molecular Entity as a Victim of Metabolic Drug-Drug Interactions--an Industry Perspective

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

Seven fatalities associated with ethylphenidate

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