Carboxyl nonsteroidal anti-inflammatory drugs are efficiently glucuronidated by microsomes of the human gastrointestinal tract

Sabolovic, Nicole; Heydel, Jean‐Marie; Li, Xin; Little, Joanna M.; Humbert, Anne-Claude; Radominska‐Pandya, Anna; Magdalou, Jacques

doi:10.1016/j.bbagen.2004.08.013

Cited by 21 publications

(10 citation statements)

References 30 publications

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“…A wide variety of UGT isoforms have been shown to be expressed in the GI tract [18,[28][29][30]. Of these, human recombinant UGT1A6 and 1A1 efficiently glucuronidated the cis-and transisomers, respectively (Figure 4), whereas UGT1A8 and 1A10, which have been reported to be intestine-specific isoforms [31], and UGT1A7 and 1A9 glucuronidated both isomers, with UGT1A9 being the most active isoform.…”

Section: Discussionmentioning

confidence: 97%

“…In the present studies, the UGT1A9, which is equally expressed in the intestine and liver, seems to be the predominant isoform involved in the glucuronidation of both resveratrol isomers. On the other hand, the UGT2B family of isoforms, especially UGT2B7 which is a major UGT expressed in human liver and intestine [30,32], were found to be not very active in glucuronidating either isomer [15]. The role of intestine in the absorption, transport and metabolism of resveratrol has also been assessed using the human intestinal Caco-2 cell line as a model [33].…”

Section: Discussionmentioning

confidence: 97%

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Resveratrol is efficiently glucuronidated by UDP‐glucuronosyltransferases in the human gastrointestinal tract and in Caco‐2 cells

Sabolovic

Humbert

Radominska‐Pandya

et al. 2006

Biopharm & Drug Disp

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Resveratrol (3, 5, 4'-trihydroxy-trans-stilbene), a natural polyphenol present in grapes and peanuts, has been reported to exert a variety of potentially therapeutic effects. The aim of this study was to determine the contribution of the gastrointestinal (GI) tract to the glucuronidation of this compound and its cis-isomer, which also occurs naturally. For this purpose, glucuronidation of the two resveratrol isomers was investigated in human microsomes prepared from: stomach, duodenum, four segments of the remaining small intestine (S-1 to S-4) and colon, and from the human intestinal cell lines Caco-2 and PD-7. cis- and trans-Resveratrol were efficiently glucuronidated in the GI tract with the formation of both 3-O- and 4'-O-glucuronides, however, the two stereoisomers were glucuronidated at different rates depending on the donor and the segment considered. Microsomes prepared from Caco-2 and PD-7 cells also efficiently glucuronidated cis-resveratrol and, to a lesser extent, the trans-isomer, however, only the 3-O-glucuronide was formed. Among the UDP-glucuronosyltransferases (UGT) that are known to be expressed in the GI tract, the isoforms UGT1A1, 1A6, 1A8, 1A9 and 1A10 were active in glucuronidating trans- and/or cis-resveratrol. The results demonstrate that the GI tract may contribute significantly to the first pass metabolism of these naturally occurring polyphenols.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 97%

Resveratrol is efficiently glucuronidated by UDP‐glucuronosyltransferases in the human gastrointestinal tract and in Caco‐2 cells

Sabolovic

Humbert

Radominska‐Pandya

et al. 2006

Biopharm & Drug Disp

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“…ml/min/g liver or intestine) is higher in the liver than in the intestine. However, it should be noted that the regional differences in glucuronidation activity [16] should be considered in the extrapolation of in vitro intrinsic glucuronidation activity from the unit of ml/min/mg protein to ml/min/g tissue. In the case of midazolam, intestinal metabolism is significantly involved in the CYP3A4-mediated metabolism in vivo [17], although, CL int in HIM is smaller than that in HLM, even on a microsomal protein concentration basis [17].…”

Section: Discussionmentioning

confidence: 99%

In vitro drug interaction between diflunisal and indomethacin via glucuronidation in humans

Mano

Usui

Kamimura

2006

Biopharm & Drug Disp

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It was reported that the plasma concentration of indomethacin was increased with concomitant oral dosages of diflunisal in humans. Both indomethacin and diflunisal are glucuronidated in humans. The effects of diflunisal on the indomethacin glucuronidation were thus investigated in vitro using human liver microsomes (HLM) and human intestine microsomes (HIM) in order to assess the drug-drug interaction. The glucuronidation of indomethacin in HLM showed atypical kinetics with Km and Ksi values of 210 and 89.5 microM, respectively, while HIM exhibited Michaelis-Menten kinetics with a Km value of 17.4 microM. Diflunisal inhibited the indomethacin glucuronidation in HLM with IC50 values ranging from 100 to 231 microM. In HIM, inhibition of the indomethacin glucuronidation by diflunisal was more potent with IC50 values of 15.2-48.7 microM. When the clinical dose of diflunisal (250 mg b.i.d.) is taken into consideration, it is expected that the diflunisal concentration in the intestine would be higher than the IC50 values for indomethacin glucuronidation in the intestine. These findings suggest that the clinical drug-drug interaction between diflunisal and indomethacin may be at least partly attributable to the inhibition of indomethacin glucuronidation by diflunisal in the intestine.

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“…In addition to glucuronidation, xenobiotics bearing a carboxylic acid group can undergo a conjugation reaction to coenzyme A, catalyzed by both mitochondrial and microsomal acyl-CoA synthetases, and resulting in the formation of acyl-CoA thioesters of the corresponding compounds. This is, for instance, the case of the 2-arylpropionic acid drug ketoprofen (KPF), which is both glucuronidated (Sabolovic et al, 2004;Sakaguchi et al, 2004) and thio-esterified with CoA (Carabaza et al, 1996). The latter metabolite appears to be an obligatory intermediate in the epimerization of chiral profen drugs, such as KPF, as well as in the formation of glycine, taurine, and carnitine conjugates (Olsen et al, 2005).…”

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confidence: 99%

Interaction of the Electrophilic Ketoprofenyl-Glucuronide and Ketoprofenyl-Coenzyme A Conjugates with Cytosolic GlutathioneS-Transferases

Osbild¹,

Bour²,

Maunit³

et al. 2007

Drug Metab Dispos

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ABSTRACT:Carboxylic acid-containing drugs are metabolized mainly through the formation of glucuronide and coenzyme A esters. These conjugates have been suspected to be responsible for the toxicity of several nonsteroidal anti-inflammatory drugs because of the reactivity of the electrophilic ester bond. In the present study we investigated the reactivity of ketoprofenyl-acylglucuronide (KPF-OG) and ketoprofenyl-acyl-coenzyme A (KPF-SCoA) toward cytosolic rat liver glutathione S-transferases (GST). We observed that KPFSCoA, but not KPF-OG inhibited the conjugation of 1-chloro-2,4-dinitrobenzene and 4-nitroquinoline N-oxide catalyzed by both purified cytosolic rat liver GST and GST from FAO and H5-6 rat hepatoma cell lines. Photoaffinity labeling with KPF-SCoA suggested that the binding of this metabolite may overlap the binding site of 4-methylumbelliferone sulfate. Furthermore, high-performance liquid chromatography and mass spectrometry analysis showed that both hydrolysis and transacylation reactions were observed in the presence of GST and glutathione. The formation of ketoprofenyl-S-acyl-glutathione could be kinetically characterized (apparent K m ‫؍‬ 196.0 ؎ 70.6 M). It is concluded that KPF-SCoA is both a GST inhibitor and a substrate of a GST-dependent transacylation reaction. The reactivity and inhibitory potency of thioester CoA derivatives toward GST may have potential implications on the reported in vivo toxicity of some carboxylic acid-containing drugs.

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Carboxyl nonsteroidal anti-inflammatory drugs are efficiently glucuronidated by microsomes of the human gastrointestinal tract

Cited by 21 publications

References 30 publications

Resveratrol is efficiently glucuronidated by UDP‐glucuronosyltransferases in the human gastrointestinal tract and in Caco‐2 cells

Resveratrol is efficiently glucuronidated by UDP‐glucuronosyltransferases in the human gastrointestinal tract and in Caco‐2 cells

In vitro drug interaction between diflunisal and indomethacin via glucuronidation in humans

Interaction of the Electrophilic Ketoprofenyl-Glucuronide and Ketoprofenyl-Coenzyme A Conjugates with Cytosolic GlutathioneS-Transferases

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