Mebolism of drugs and other xenobiotics in the gut lumen and wall

Ilett, Kenneth F.; Tee, Lisa; Reeves, Philip T.; Minchin, Rodney F.

doi:10.1016/0163-7258(90)90036-2

Cited by 181 publications

(85 citation statements)

References 206 publications

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“…Moreover, parasitoses in young animals can be especially dangerous [22]. We tested the effect of FLU and gender not only on hepatic enzymes but also on enzymes of intestinal mucosa, as metabolism in the gut wall can decrease the bioavailability and pharmacological effects of a wide variety of orally administered drugs [21].…”

Section: Discussionmentioning

confidence: 99%

Activities of biotransformation enzymes and flubendazole metabolism in lambs (Ovis aries): effect of gender and flubendazole therapy

Bártíková

Křížová

Štěpničková

et al. 2010

Pharmacological Reports

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Abstract:The effect of flubendazole (FLU) therapy on in vitro FLU biotransformation and the activities of selected biotransformation enzymes were investigated in male and female lambs. Four experimental groups were used: control (untreated) ewes and rams and FLU-treated ewes and rams (orally, 15 mg/kg per day, for three consecutive days). Subcellular fractions were prepared from liver and intestinal mucosa 24 h after the final dosage was administered. Activities of cytochromes P450 (CYP), flavine monooxygenases (FMO), carbonyl reducing enzymes, UDP-glucuronosyl transferase (UGT) and glutathione S-transferase were tested. Significant gender differences were observed for FMO-mediated activity (2-fold higher in ram lambs) and UGT activity (up to 30% higher in ewe lambs), but no gender differences were observed in FLU metabolism. FLU-treatment of lambs moderately changed the activities of some CYPs, FMO, and UGT in liver microsomes. In vitro FLU reduction was not altered in the liver, but was slightly higher in the small intestine of FLU pre-treated lambs. This correlated with the higher carbonyl reductase activities measured in the gut mucosa of these animals.

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Section: Discussionmentioning

confidence: 99%

Activities of biotransformation enzymes and flubendazole metabolism in lambs (Ovis aries): effect of gender and flubendazole therapy

Bártíková

Křížová

Štěpničková

et al. 2010

Pharmacological Reports

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“…Examples are the reduction of omeprazole and digoxin, hydrolysis of lactulose and sorivudine, acetylation of 5-aminosalicylic acid, proteolysis of www.intechopen.com insulin and calcitonin and N-demethylation of methamphetamine. Additionally, demethylation, deamination, decarboxylation and dehalogenation reactions have also been described, next to other reactions such as aromatization, esterification and N-nitrosation (Ilett et al, 1990). Microbial metabolism is not only confined to drugs, but also targets contaminants.…”

Section: Direct Microbial Metabolism Influences Final Activity Profilesmentioning

confidence: 99%

“…Compounds that have been absorbed in the intestine and subsequently detoxified are usually conjugated with polar groups (glucuronic acid, glycine, sulfate, glutathion, and taurine) in the liver prior to secretion with the bile (Ilett et al, 1990). After released in the intestinal lumen, these phase II biotransformation products may be hydrolyzed again by bacterial enzymes such as -glucuronidase, sulfatase, and other glycosidases.…”

Section: Microbial Metabolism Interferes With the Enterohepatic Circumentioning

confidence: 99%

“…Ilett et al (1990) have already indicated that gut bacterial metabolism is reductive, hydrolytic and even of degradative nature with a strong potential for both bioactivation and detoxification of xenobiotics. The latter is in contrast to the oxidative and conjugative reactions from the phase I and II enzymes in the enterocytes and hepatocytes (Ilett et al, 1990). Moreover, the intestinal microbiota interferes with the human biotransformation process through the enterohepatic circulation of xenobiotic compounds what may reverse the detoxification cycle of the liver.…”

Section: The Microbial Metabolic Perspectivementioning

confidence: 99%

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The Gut Microbiota as Target for Innovative Drug Development: Perspectives and a Case Study of Inflammatory Bowel Diseases

Vermeiren¹,

Possemiers²,

Marzorati³

et al. 2011

Drug Development - A Case Study Based Insight Into Modern Strategies

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“…23,24 A recent study has shown that human liver can reduce CB1954 to N-hydroxylamine intermediates in vitro.…”

mentioning

confidence: 99%

E. coli nitroreductase/CB1954 gene-directed enzyme prodrug therapy: role of arylamine N-acetlytransferase 2

Mitchell

Minchin

2008

Cancer Gene Ther

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Gene-directed enzyme prodrug therapy is a promising approach to the local management of cancer and a number of gene prodrug combinations have entered clinical trials. The antitumor activity of Escherichia coli nitroreductase (NTR) in combination with the prodrug CB1954 relies on the reduction of the nitro groups to reactive N-hydroxylamine intermediates that are toxic in proliferating and nonproliferating cells. We examined whether secondary metabolic activation of the N-hydroxylamines by sulfotransferases or acetyltransferases altered cell responsiveness to the drug. We evaluated the coexpression of NTR with the human cytosolic sulfotransferases SULT1A1, 1A2, 1A3, 1E1 and 2A1, or the human arylamine N-acetyltransferases NAT1 and NAT2 on SKOV3 cell survival. Only NAT2 significantly altered the toxicity of CB1954, decreasing the IC 50 16-fold from 0.61 to 0.04 mM. These results suggest that one or more of the N-hydroxyl metabolites are a substrate for O-acetylation by NAT2. We also examined the bystander effect of SKOV3 cells expressing NTR or NTR plus NAT2. Addition of the acetyltransferase resulted in a significant decreased bystander effect (P40.01), possibly due to a lower concentration of reactive metabolites in the culture medium. These results suggest that a combination of bacterial NTR and NAT2 may provide a greater clinical response at therapeutic concentrations of CB1954 provided the reduction in bystander effect is not clinically significant. Moreover, endogenous NAT2, which is localized predominantly in the liver and gut, may be involved in the dose-limiting hepatic toxicity and gastrointestinal side effects seen in patients treated with the higher doses of CB1954.

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Mebolism of drugs and other xenobiotics in the gut lumen and wall

Cited by 181 publications

References 206 publications

Activities of biotransformation enzymes and flubendazole metabolism in lambs (Ovis aries): effect of gender and flubendazole therapy

Activities of biotransformation enzymes and flubendazole metabolism in lambs (Ovis aries): effect of gender and flubendazole therapy

The Gut Microbiota as Target for Innovative Drug Development: Perspectives and a Case Study of Inflammatory Bowel Diseases

E. coli nitroreductase/CB1954 gene-directed enzyme prodrug therapy: role of arylamine N-acetlytransferase 2

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