Human arylacetamide deacetylase is responsible for deacetylation of rifamycins: Rifampicin, rifabutin, and rifapentine

Nakajima, Akinori; Fukami, Tatsuki; Kobayashi, Yuki; Watanabe, Akinobu; Nakajima, Miki; Yokoi, Tsuyoshi

doi:10.1016/j.bcp.2011.08.003

Cited by 112 publications

(105 citation statements)

References 34 publications

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“…The present clinical interaction study also aimed to determine whether rifampin might affect the major metabolic pathway of BRV, namely, its hydrolysis into BRV-AC. Such an interaction could not be a priori ruled out, as rifampin had been reported to be a substrate (Nakajima et al, 2011), inducer (Sarma et al, 1986), or inhibitor (Hernandez et al, 1997) of some hydrolytic enzymes. Further, the enzyme responsible for BRV hydrolysis was unknown.…”

Section: Brivaracetam [(2s)-2-[(4r)-2-oxo-4-propylpyrrolidinyl] Butanmentioning

confidence: 99%

Effect of Rifampin on the Disposition of Brivaracetam in Human Subjects: Further Insights into Brivaracetam Hydrolysis

Stockis

Watanabe

Scheen

et al. 2016

Drug Metabolism and Disposition

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Brivaracetam (BRV) is a high-affinity synaptic vesicle protein 2A ligand developed for the treatment of uncontrolled partial-onset seizures. The present phase I, open-label, two-way crossover study was designed to assess the effect of rifampin on the pharmacokinetics of BRV and its hydroxy (BRV-OH), acid (BRV-AC), and hydroxy acid (BRV-OHAC) metabolites. Twenty-six healthy subjects received BRV (150-mg single oral dose) either alone or following 5 days of rifampin 600 mg/day. BRV and its metabolites were examined for their plasma profiles and urinary excretion. Pharmacokinetic modeling was developed to estimate the rate constants of the various metabolic routes. Parallel in vitro assays were conducted to characterize the hydrolysis of BRV to BRV-AC as well as to identify any potential effect of rifampin on the hydrolysis reaction. Rifampin did not significantly affect the maximum plasma concentration (C max ) of BRV, but decreased its area under the curve (AUC) by 45%. In addition, rifampin significantly increased the AUC of BRV-OH (+109%), decreased the AUC of BRV-AC (253%), but had little effect on BRV-OHAC (210%). In vitro assays showed that the major urinary metabolite BRV-AC (33% of the dose) was likely to be formed by amidase EC 3.5.1.4. In vitro data indicated that the enzyme was not significantly inhibited nor induced by rifampin. Modeling confirmed that all of the observed changes in vivo were secondary to the induction of the CYP2C19-mediated hydroxylation of BRV to BRV-OH (3.7-fold increase in the rate constant).

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Section: Brivaracetam [(2s)-2-[(4r)-2-oxo-4-propylpyrrolidinyl] Butanmentioning

confidence: 99%

Effect of Rifampin on the Disposition of Brivaracetam in Human Subjects: Further Insights into Brivaracetam Hydrolysis

Stockis

Watanabe

Scheen

et al. 2016

Drug Metabolism and Disposition

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“…Esterases, which are involved in bioactivation of ester-based prodrugs and inactivation of clinical drugs as well, are typically represented by carboxylesterases (CES) (Satoh and Hosokawa, 2006;Hosokawa, 2008), cholinesterases (Taylor, 1991;Taylor and Radic, 1994), and paraoxonases (Draganov and La Du, 2004). In addition, recent works revealed several valuable aspects of other esterases responsible for drug hydrolysis: valacyclovirase as a bioactivating hydrolase for the amino-acid ester prodrugs valacyclovir and valganciclovir (Kim et al, 2003;Lai et al, 2008); arylacetamide deacetylase as a hydrolase being associated with organ toxicities of clinical drugs such as flutamide, phenacetine, and rifamycins (Watanabe et al, 2009;Watanabe et al, 2010;Nakajima et al, 2011); and a/b hydrolase domain-containing 10 (ABHD10), which functions as the detoxification enzyme of mycophenolic acid acyl-glucuronide (Iwamura et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Different Hydrolases Involved in Bioactivation of Prodrug-Type Angiotensin Receptor Blockers: Carboxymethylenebutenolidase and Carboxylesterase 1

et al. 2013

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Olmesartan medoxomil (OM) is a prodrug-type angiotensin II type 1 receptor blocker (ARB). We recently identified carboxymethylenebutenolidase homolog (CMBL) as the responsible enzyme for OM bioactivation in humans. In the present study, we compared the bioactivating properties of OM with those of other prodrug-type ARBs, candesartan cilexetil (CC) and azilsartan medoxomil (AM), by focusing on interspecies differences and tissue specificity. In invitro experiments with pooled tissue subcellular fractions of mice, rats, monkeys, dogs, and humans, substantial OM-hydrolase activities were observed in cytosols of the liver, intestine, and kidney in all the species tested except for dog intestine, which showed negligible activity, whereas lung cytosols showed relatively low activities compared with the other tissues. AM-hydrolase activities were well correlated with the OM-hydrolase activities. In contrast, liver microsomes exhibited the highest CC-hydrolase activity among various tissue subcellular fractions in all the species tested. As a result of Western blot analysis with the tissue subcellular fractions, the band intensities stained with anti-human CMBL and carboxylesterase 1 (CES1) antibodies well reflected OM-and AM-hydrolase activities and CC-hydrolase activity, respectively, in animals and humans. Recombinant human CMBL and CES1 showed significant AM-and CC-hydrolase activities, respectively, whereas CC hydrolysis was hardly catalyzed with recombinant carboxylesterase 2 (CES2). In conclusion, OM is bioactivated mainly via intestinal and additionally hepatic CMBL not only in humans but also in mice, rats, and monkeys, while CC is bioactivated via hepatic CES1 rather than intestinal enzymes, including CES2. AM is a substrate for CMBL.

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“…The rifampicin hydrolase activity, which is a marker of AADAC enzyme activity, was determined according to our previous study (Nakajima et al, 2011). The concentration of enzyme sources (HLH and Sf21 cell homogenates expressing human AADAC) was 0.5 mg/ml.…”

Section: Methodsmentioning

confidence: 99%

Contributions of Arylacetamide Deacetylase and Carboxylesterase 2 to Flutamide Hydrolysis in Human Liver

Kobayashi

Fukami²,

Shimizu³

et al. 2012

Drug Metab Dispos

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ABSTRACT:Flutamide, an antiandrogen drug, is widely used for the treatment of prostate cancer. The major metabolic pathways of flutamide are hydroxylation and hydrolysis. The hydrolyzed metabolite, 5-amino-2-nitrobenzotrifluoride (FLU-1), is further metabolized to N-hydroxy FLU-1, an assumed hepatotoxicant. Our previous study demonstrated that arylacetamide deacetylase (AADAC), one of the major serine esterases expressed in the human liver and gastrointestinal tract, catalyzes the flutamide hydrolysis. However, the enzyme kinetics in human tissue microsomes were not consistent with the kinetics by recombinant human AADAC. Thus, it seemed that AADAC is not the sole enzyme responsible for flutamide hydrolysis in human. In the present study, we found that recombinant carboxylesterase (CES) 2 could hydrolyze flutamide at low concentrations of flutamide. In the inhibition assay, the flutamide hydrolase activities at a flutamide concentration of 5 M in human liver and jejunum microsomes were strongly inhibited by a selective CES2 inhibitor, 10 M loperamide, with the residual activities of 22.9 ؎ 3.5 and 18.6 ؎ 0.7%, respectively. These results suggest that CES2 is also involved in the flutamide hydrolysis in human tissues. Using six individual human livers, the contributions of AADAC and CES2 to flutamide hydrolysis were estimated by using the relative activity factor. The relative contribution of CES2 was approximately 75 to 99% at the concentration of 5 M flutamide. In contrast, the relative contribution of AADAC increased in parallel with the concentration of flutamide. Thus, CES2, rather than AA-DAC, largely contributed to the flutamide hydrolysis in clinical therapeutics.

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Human arylacetamide deacetylase is responsible for deacetylation of rifamycins: Rifampicin, rifabutin, and rifapentine

Cited by 112 publications

References 34 publications

Effect of Rifampin on the Disposition of Brivaracetam in Human Subjects: Further Insights into Brivaracetam Hydrolysis

Effect of Rifampin on the Disposition of Brivaracetam in Human Subjects: Further Insights into Brivaracetam Hydrolysis

Different Hydrolases Involved in Bioactivation of Prodrug-Type Angiotensin Receptor Blockers: Carboxymethylenebutenolidase and Carboxylesterase 1

Contributions of Arylacetamide Deacetylase and Carboxylesterase 2 to Flutamide Hydrolysis in Human Liver

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