The Inhibitory Effect of Ciprofloxacin on the β‐Glucuronidase‐mediated Deconjugation of the Irinotecan Metabolite SN‐38‐G

Abstract

Abstract:The enterohepatic recycling of a drug consists of its biliary excretion and intestinal reabsorption, which is sometimes accompanied by hepatic conjugation and intestinal deconjugation reactions. b-Glucuronidase, an intestinal bacteria-produced enzyme, can break the bond between a biliary excreted drug and glucuronic acid. Antibiotics such as ciprofloxacin can reduce the enterohepatic recycling of glucuronide-conjugated drugs. In this study, we established an in vitro system to evaluate the b-glucuronidase-mediated deconjugation of the irinotecan metabolite SN-38-G to its active SN-38 form and the effect of ciprofloxacin thereon. SN-38 formation increased in a time-dependent manner from 5 to 30 min. in the presence of b-glucuronidase. Ciprofloxacin and phenolphthalein-b-D-glucuronide (PhePG), a typical b-glucuronidase substrate, significantly decreased SN-38-G deconjugation and, hence SN-38 formation. Similarly, the antibiotics enoxacin and gatifloxacin significantly inhibited the conversion of SN-38-G to SN-38, which was not observed for levofloxacin, streptomycin, ampicillin and amoxicillin/clavulanate. Ciprofloxacin showed a dose-dependent inhibitory effect on the b-glucuronidase-mediated conversion of SN-38-G to SN-38 with a half-maximal inhibitory concentration (IC 50 ) value of 83.8 lM. PhePG and ciprofloxacin afforded the inhibition in a competitive and non-competitive manner, respectively. These findings suggest that the reduction in the serum SN-38 concentration following co-administration of ciprofloxacin during irinotecan treatment is due, at least partly, to the decreased enterohepatic circulation of SN-38 through the non-competitive inhibition of intestinal b-glucuronidase-mediated SN-38-G deconjugation.Irinotecan is an anti-tumour drug frequently used in clinical practice for the treatment of various carcinomas such as colorectal cancer [1] and lung cancer [2]. In vivo, irinotecan is converted to the active metabolite SN-38 (7-ethyl-10-hydroxycamptothecin) by carboxylesterase in the liver microsomes. SN-38 exhibits anti-tumour effects by inhibiting type I topoisomerases in tumour cells [3]. Moreover, SN-38 is excreted into the gastrointestinal tract as a glucuronic acid conjugate (hereinafter SN-38-G) mainly via bile through the hepatic metabolic enzyme UDP-glucuronosyltransferase 1-1 (UGT1A1). SN-38-G is subsequently converted into its active form (SN-38) through deconjugation mediated by enteric bacteria-derived b-glucuronidase [4]. The presence of SN-38 in the gastrointestinal tract may cause diarrhoea as side effect by directly impairing certain functions of the gastrointestinal tract. Thus, in clinical practice, drugs that inhibit the deconjugation of glucuronic acid in the gastrointestinal tract are sometimes co-administered as supportive therapy to reduce SN-38-related side effects [5]. Diarrhoeal is a dose-limiting factor in irinotecan treatment; long-term diarrhoea prevents the use of a sufficient dose of irinotecan, which may hinder irinotecan's therapeutic efficacy. Thus far, we ...

Ciprofloxacin blocked enterohepatic circulation of diclofenac and alleviated NSAID-induced enteropathy in rats partly by inhibiting intestinal β-glucuronidase activity

“…A previous study showed that ciprofloxacin inhibited the hydrolysis of mycophenolic acid glucuronide to mycophenolic acid by inhibiting β-glucuronidase [17] . A recent study demonstrated an inhibitory effect of ciprofloxacin on the β-glucuronidase-mediated deconjugation of the irinotecan metabolite SN-38-G [33] . The present study also showed that the β-glucuronidase activity gradually increased along the proximal small intestine toward the ileal valve in CON rats.…”

Gut microbiota modulation of chemotherapy efficacy and toxicity

“…Furthermore, the bacterial enzyme contains a 'bacterial loop' not found in the human form of the enzyme, enabling highly selective inhibitors of the bacterial enzyme to be developed, two of which blocked the active site of the E. coli β-glucuronidase, but had no effect on bovine liver glucuronidase. The quinolone antibiotic ciprofloxacin has also been shown to inhibit this enzyme, and low doses of amoxapine, a known inhibitor of bacterial β-glucuronidases, suppressed diarrhoea associated with irinotecan in a rat model 46,47 . An analysis of crystal structures of representative β-…”

Gut microbiota, chemotherapy and the host: the influence of the gut microbiota on cancer treatment

“…However, gut microbes are not always beneficial. An increased understanding of gut microbial metabolism has revealed contributions to drug toxicity such as mucositis and neuropathy that can even prove fatal [ 22 , 23 , 25 , 26 , 43 ]. The delicate equilibrium of bacterial community structure and host-microbiota interactions is also disrupted by chemotherapeutic administration, which promotes inflammation and mucosal destruction, and is associated with adverse outcome [ 31 – 34 ].…”

“…Microbiome characterisation may, therefore, identify patients at risk of irinotecan-induced mucositis while manipulation of the microbiota may provide novel therapeutic options. Ciprofloxacin and low doses of amoxapine have been shown to be effective in the suppression of bacterial ß-glucuronidase activity and mucositis [ 22 , 23 ]. Furthermore, bacterial ß-glucuronidases possess unique motifs relative to their human counterparts, which pave the way for the development of bacterial-specific inhibitors [ 22 – 24 ].…”

“…These include selective antibiotic therapy (targeting specific bacterial species), probiotic therapy (administration of living micro-organisms), pre-biotic therapy (compounds administered to encourage the functions of certain microbiota) and post-biotic therapy (use of nonviable microbial products to exert immunological or biological activity) [ 39 ]. Use of both antibiotic therapies and probiotic VSL#3 administration has been shown to reduce the incidence of irinocetan-induced mucositis in rodent models [ 23 , 40 ]. Various studies on probiotic administration during chemotherapy have also suggested that they may reduce the incidence of systemic infection [ 41 ].…”