Effects of bacterial and presystemic nitroreductase metabolism of 2-chloro-5-nitro-N-phenylbenzamide on its mutagenicity and bioavailability

Kapetanović, Izet M.; Lyubimov, Aleksander V.; Kabirova, Elena V.; Kabirov, Kasim K.; Rasay, Laura; Swezey, Robert R.; Green, Carol; Kopelovich, Levy

doi:10.1016/j.cbi.2012.03.002

Cited by 6 publications

(5 citation statements)

References 31 publications

(33 reference statements)

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“…Albeit GW9662 was rapidly cleared and distributed in tissue after i.v. injection, GW9662 was found in plasma at low concentration [33]. Moreover, GW9662 is a selective covalent and irreversible antagonist of full-length PPARγ with IC50 value of 3.3 nM [34].…”

Section: Animals and Treatmentmentioning

confidence: 97%

GW9662, a peroxisome proliferator-activated receptor gamma antagonist, attenuates the development of non-alcoholic fatty liver disease

et al. 2022

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Section: Animals and Treatmentmentioning

confidence: 97%

GW9662, a peroxisome proliferator-activated receptor gamma antagonist, attenuates the development of non-alcoholic fatty liver disease

et al. 2022

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“…Bacterial nitroreduction reactions are of considerable interest because they can significantly impact the pharmacologic activity of nitroaromatic drugs such as chloramphenicol (Roldan et al, 2008), 2-chloro-5-nitro-N-phenylbenzamide (GW9662), (Kapetanovic et al, 2012), nitrobenzodiazepine (LinWu et al, 2012), and CB1954 [5-(aziridin-1-yl)-2,4-dinitrobenzamide] (Prosser et al, 2010). Chloramphenicol, an antibiotic, was one of the first drugs discovered to be a substrate of bacterial nitroreductases (Roldan et al, 2008).…”

Section: Impact Of the Gut Microbiome On The Metabolism And Pharmacokmentioning

confidence: 99%

“…GW9662 is an antagonist of peroxisome proliferator activated receptor g and a potential chemopreventive agent. The predominant metabolite of GW996 in the plasma has been identified as an amine metabolite, and its nitroreduction by bacterial nitroreductases can significantly alter its mutagenicity (Kapetanovic et al, 2012). Study of the nitroreduction of nitrobenzodiazepine, an addictive sedative used to treat anxiety and sleep disorders, has led to further characterization of bacterial nitroreductases involved in its metabolism (LinWu et al, 2012).…”

Section: Impact Of the Gut Microbiome On The Metabolism And Pharmacokmentioning

confidence: 99%

Drug Metabolism by the Host and Gut Microbiota: A Partnership or Rivalry?

Swanson

2015

Drug Metab Dispos

138

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The importance of the gut microbiome in determining not only overall health, but also in the metabolism of drugs and xenobiotics, is rapidly emerging. It is becoming increasingly clear that the gut microbiota can act in concert with the host cells to maintain intestinal homeostasis, cometabolize drugs and xenobiotics, and alter the expression levels of drug-metabolizing enzymes and transporters and the expression and activity levels of nuclear receptors. In this myriad of activities, the impact of the microbiota may be beneficial or detrimental to the host. Given that the interplay between the gut microbiota and host cells is likely subject to high interindividual variability, this work has tremendous implications for our ability to predict accurately a particular drug's pharmacokinetics and a given patient population's response to drugs. In this issue of Drug Metabolism and Disposition, a series of articles is presented that illustrate the progress and challenges that lie ahead as we unravel the intricacies associated with drug and xenobiotic metabolism by the gut microbiota. These articles highlight the underlying mechanisms that are involved and the use of in vivo and in vitro approaches that are currently available for elucidating the role of the gut microbiota in drug and xenobiotic metabolism. These articles also shed light on exciting new avenues of research that may be pursued as we consider the role of the gut microbiota as an endocrine organ, a component of the brain-gut axis, and whether the gut microbiota is an appropriate and amenable target for new drugs.

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“…Increasing evidences have been rapidly emerging that gut microbiota expresses a variety of enzymes, which could alter the activity and absorption of drugs by modifying their chemical structures 23 . It was reported that more than 30 commonly prescribed drugs were metabolically altered by the enzymes in gut microbiota 24 , 25 , 26 , including methylase/demethylase, β -glucuronidase, nitroreductase, azoreductase, and so on 27 , 28 , 29 , 30 , 31 . For example, sulfasalazine, a sulfa drug used for the treatment of ulcerative colitis, is absorbed in the colon and converted to its pharmacologically active form of 5-amino 5-salicylic acid by azoreductase in gut microbiota 32 , 33 .…”

Section: Discussionmentioning

confidence: 99%

Gut microbiota mediates the absorption of FLZ, a new drug for Parkinson's disease treatment

Shang

Zang

et al. 2021

Acta Pharmaceutica Sinica B

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The gut microbiota plays an important role in regulating the pharmacokinetics and pharmacodynamics of many drugs. FLZ, a novel squamosamide derivative, has been shown to have neuroprotective effects on experimental Parkinson's disease (PD) models. FLZ is under phase Ⅰ clinical trial now, while the underlying mechanisms contributing to the absorption of FLZ are still not fully elucidated. Due to the main metabolite of FLZ was abundant in feces but rare in urine and bile of mice, we focused on the gut microbiota to address how FLZ was metabolized and absorbed. In vitro studies revealed that FLZ could be exclusively metabolized to its major metabolite M1 by the lanosterol 14 alpha-demethylase (CYP51) in the gut microbiota, but was almost not metabolized by any other metabolism-related organs, such as liver, kidney, and small intestine. M1 was quickly absorbed into the blood and then remethylated to FLZ by catechol O -methyltransferase (COMT). Notably, dysbacteriosis reduced the therapeutic efficacy of FLZ on the PD mouse model by inhibiting its absorption. The results show that the gut microbiota mediate the absorption of FLZ through a FLZ–M1–FLZ circulation. Our research elucidates the vital role of the gut microbiota in the absorption of FLZ and provides a theoretical basis for clinical pharmacokinetic studies and clinical application of FLZ in the treatment of PD.

show abstract

Effects of bacterial and presystemic nitroreductase metabolism of 2-chloro-5-nitro-N-phenylbenzamide on its mutagenicity and bioavailability

Cited by 6 publications

References 31 publications

GW9662, a peroxisome proliferator-activated receptor gamma antagonist, attenuates the development of non-alcoholic fatty liver disease

GW9662, a peroxisome proliferator-activated receptor gamma antagonist, attenuates the development of non-alcoholic fatty liver disease

Drug Metabolism by the Host and Gut Microbiota: A Partnership or Rivalry?

Gut microbiota mediates the absorption of FLZ, a new drug for Parkinson's disease treatment

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