Inhibition of intestinal microflora β-glucuronidase modifies the distribution of the active metabolite of the antitumor agent, irinotecan hydrochloride (CPT-11) in rats

Takasuna, Kiyoshi; Hagiwara, Toshihiko; Hirohashi, Masaaki; Kato, Michiyuki; Nomura, Mamoru; Nagai, Eiichi; Yokoi, Tsuyoshi; Kamataki, Tetsuya

doi:10.1007/s002800050818

Cited by 119 publications

(109 citation statements)

References 18 publications

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“…TMA is absorbed and oxidized by hepatic flavin monooxygenases to form TMA N-oxide (TMAO), a metabolite linked to increased accumulation of cholesterol in macrophages, foam cell deposition, and atherosclerosis (72). Clinical studies have confirmed that TMAO production is also dependent on the gut microbiome in humans, with plasma TMAO levels suppressed during antibiotic treatment and restored upon contributing to dose-limiting gastrointestinal side effects (47,48). Broad-spectrum antibiotics and dietary fiber consumption have been proposed as general strategies that might reduce the toxicity of irinotecan (49,50), but both of these interventions can have widespread impacts on the gut microbiota (51,52).…”

Section: R E V I E W S E R I E S : G U T M I C R O B I O M Ementioning

confidence: 99%

Host-microbial interactions in the metabolism of therapeutic and diet-derived xenobiotics

Carmody¹,

Turnbaugh²

2014

J. Clin. Invest.

214

145

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Section: R E V I E W S E R I E S : G U T M I C R O B I O M Ementioning

confidence: 99%

Host-microbial interactions in the metabolism of therapeutic and diet-derived xenobiotics

Carmody¹,

Turnbaugh²

2014

J. Clin. Invest.

214

145

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“…[Takasuna et al 1998;Stringer et al 2007Stringer et al , 2008. (3) The distribution and severity of histological damage within the rat intestine after administration of irinotecan has been correlated to the luminal ß-glucuronidase activity in rodents [Takasuna et al 1998;Fittkau et al 2004]. (4) Irinotecan causes severe colonic damage (increased apoptosis, crypt hypoplasia and dilation) with accompanying excessive mucous secretion, as well as the usual chemotherapy-induced small intestinal damage, like villous atrophy and crypt hypoplasia.…”

Section: Pathophysiology Of Irinotecan-induced Diarrheamentioning

confidence: 99%

“…The bacterial ß-glucuronidase then deconjugates SN38G to the active form SN38 at an increased rate causing significant damage and diarrhea. [Takasuna et al 1998;Stringer et al 2007Stringer et al , 2008. (3) The distribution and severity of histological damage within the rat intestine after administration of irinotecan has been correlated to the luminal ß-glucuronidase activity in rodents [Takasuna et al 1998;Fittkau et al 2004].…”

Section: Pathophysiology Of Irinotecan-induced Diarrheamentioning

confidence: 99%

Review: Chemotherapy-induced diarrhea: pathophysiology, frequency and guideline-based management

2009

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Diarrhea is one of the main drawbacks for cancer patients. Possible etiologies could be radiotherapy, chemotherapeutic agents, decreased physical performance, graft versus host disease and infections. Chemotherapy-induced diarrhea (CID) is a common problem, especially in patients with advanced cancer. The incidence of CID has been reported to be as high as 5080% of treated patients (30% CTC grade 35), especially with 5-fluorouracil bolus or some combination therapies of irinotecan and fluoropyrimidines (IFL, XELIRI). Regardless of the molecular targeted approach of tyrosine kinase inhibitors and antibodies, diarrhea is a common side effect in up to 60% of patients with up to 10% having severe diarrhea. Furthermore, the underlying pathophysiology is still under investigation. Despite the number of clinical trials evaluating therapeutic or prophylactic measures in CID, there are just three drugs recommended in current guidelines: loperamide, deodorized tincture of opium and octreotide. Newer strategies and more effective agents are being developed to reduce the morbidity and mortality associated with CID. Recent research focusing on the prophylactic use of antibiotics, budesonide, probiotics or activated charcoal still have to define the role of these drugs in the routine clinical setting. Whereas therapeutic management and clinical work-up of patients presenting with diarrhea after chemotherapy are rather well defined, prediction and prevention of CID is an evolving field. Current research focuses on establishing predictive factors for CID like uridine diphosphate glucuronosyltransferase-1A1 polymorphisms for irinotecan or dihydropyrimidine-dehydrogenase insufficiency for fluoropyrimidines.

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“…Prophylactic use of antibiotics in rats reduced both SN-38 concentration in the intestinal lumen and diarrhea (11). Administration of antibiotics in man reduced both fecal h-glucuronidase activity and the SN-38/SN-38 glucuronide ratio (12) although available data on the efficacy of this prophylactic treatment on diarrhea are inconclusive (12,13).…”

mentioning

confidence: 99%

Intestinal microflora and digestive toxicity of irinotecan in mice.

Brandi

Dabard

Raibaud

et al. 2006

Clinical Cancer Research

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Purpose: Delayed diarrhea is the most important side effect of irinotecan. The aim of this study was to investigate the role of intestinal microflora on the induction of systemic and intestinal toxicity and diarrhea, studying germ-free and holoxenic mice i.p. injected with irinotecan. Experimental Design: To evaluate the lethal dose, starting with 100 mg/kg/4 d, we treated the holoxenic mice with100, 80, and 60 mg/kg/4 d and germ-free mice with 60, 80,100, and150 mg/ kg/4 d. We recorded the percentage of dead animals, diarrhea, and the epithelial damage to the jejunum, ileum, cecum, and colon at optical and scanning electron microscopy. Results: Germ-free mice were more resistant to irinotecan than the holoxenic group. The lethal dose was between 60 and 80 mg of irinotecan for holoxenic mice and z150 mg for the germ-free. The intestinal damage score was higher in holoxenic than germ-free mice at 100 mg and equally diffuse in the small and large bowel. The damage in germ-free mice was less severe (8 of 40 samples) prevailing in the ileum. The differences were significant for all sites (jejunum, P < 0.001; ileum, P = 0.012; cecum, P = 0.001; colon, P < 0.001). No damage was found in germ-free mice at 60 mg. Diarrhea was present in all 100 and 80 mg holoxenic mice and in 19 of 20 cases at 60 mg whereas it was absent in 60 mg or sporadic in 80 and 100 mg germ-free mice. Conclusions: The intestinal microflora plays a key role in the intestinal toxicity of irinotecan.

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Inhibition of intestinal microflora β-glucuronidase modifies the distribution of the active metabolite of the antitumor agent, irinotecan hydrochloride (CPT-11) in rats

Cited by 119 publications

References 18 publications

Host-microbial interactions in the metabolism of therapeutic and diet-derived xenobiotics

Host-microbial interactions in the metabolism of therapeutic and diet-derived xenobiotics

Review: Chemotherapy-induced diarrhea: pathophysiology, frequency and guideline-based management

Intestinal microflora and digestive toxicity of irinotecan in mice.

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