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 ...
The interaction between mycophenolate (MPA) and quinolone antibiotics such as ciprofloxacin is considered to reduce the enterohepatic recycling of MPA, which is biotransformed in the intestine from MPA glucuronide (MPAG) conjugate excreted via the biliary system; however, the molecular mechanism underlying this biotransformation of MPA is still unclear. In this study, an in vitro system was established to evaluate β-glucuronidase-mediated deconjugation and to examine the influence of ciprofloxacin on the enzymatic deconjugation of MPAG and MPA resynthesis. Resynthesis of MPA via deconjugation of MPAG increased in a time-dependent manner from 5 to 60 min in the presence of β-glucuronidase. Ciprofloxacin and phenolphthalein-β-d-glucuronide (PhePG), a typical β-glucuronidase substrate, significantly decreased the production of MPA from MPAG in the β-glucuronidase-mediated deconjugation system. In addition, enoxacin significantly inhibited the production of MPA from MPAG, while levofloxacin and ofloxacin had no inhibitory effect on MPA synthesis. Pharmacokinetic analysis revealed that ciprofloxacin showed a dose-dependent inhibitory effect on MPA production from MPAG via β-glucuronidase with a half-maximal inhibitory concentration (IC50 ) value of 30.4 µm. While PhePG inhibited the β-glucuronidase-mediated production of MPA from MPAG in a competitive manner, ciprofloxacin inhibited MPA synthesis via noncompetitive inhibition. These findings suggest that the reduction in the serum MPA concentration during the co-administration of ciprofloxacin is at least in part due to the decreased enterohepatic circulation of MPA because of noncompetitive inhibition of deconjugation of MPAG by intestinal β-glucuronidase.
Objective Methicillin-resistant (MR) Staphylococcus aureus bacteremia (SAB) is associated with higher mortality rates than methicillin-susceptible (MS) SAB. This study assessed potential predictors of mortality and evaluated the association of methicillin resistance with mortality in patients with SAB. Methods We conducted a retrospective cohort study in patients with hospital-acquired SAB, from 2009 to 2018. Clinical features of patients with MR-SAB were compared with those of patients with MS-SAB and predictors of 30-day mortality were determined using Cox regression analysis. Results Among 162 patients, 56.8% had MR-SAB. Overall 30-day mortality was 19.1%; MR-SAB had higher mortality (25.0%) than MS-SAB (11.4%). Univariate analysis highlighted long-term hospitalization, prior antibiotics use, and delayed initiation of appropriate antibiotics as risk factors. Cox regression analysis showed that respiratory tract source, Pitt bacteremia score, Charlson comorbidity index, and appropriate antibiotic therapy within 24 hours were independently and significantly associated with 30-day mortality outcome. Conclusions Methicillin resistance was not an independent risk factor for mortality in patients with SAB. Early, appropriate antibiotic treatment is an important prognostic factor.
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