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

Abstract

Aim: Diclofenac is a non-steroidal anti-inflammatory drug (NSAID), which may cause serious intestinal adverse reactions (enteropathy). In this study we investigated whether co-administration of ciprofloxacin affected the pharmacokinetics of diclofenac and diclofenacinduced enteropathy in rats. Methods: The pharmacokinetics of diclofenac was assessed in rats after receiving diclofenac (10 mg/kg, ig, or 5 mg/kg, iv), with or without ciprofloxacin (20 mg/kg, ig) co-administered. After receiving 6 oral doses or 15 intravenous doses of diclofenac, the rats were sacrificed, and small intestine was removed to examine diclofenac-induced enteropathy. β-Glucuronidase activity in intestinal content, bovine liver and E coli was evaluated. Results: Following oral or intravenous administration, the pharmacokinetic profile of diclofenac displayed typical enterohepatic circulation, and co-administration of ciprofloxacin abolished the enterohepatic circulation, resulted in significant reduction in the plasma content of diclofenac. In control rats, β-glucuronidase activity in small intestinal content was region-dependent: proximal intestine<distal intestine<ileal valve. Administration of ciprofloxac caused significant reduction of β-glucuronidase activity in distal small intestine, and particularly in ileal valve. Furthermore, ciprofloxacin (10-2000 μmol/L) dose-dependently inhibited β-glucuronidase activity in distal small intestine content or E coli incubated in vitro, but did not affect that in proximal small intestine content or bovine liver incubated in vitro. After receiving 6 oral doses or 15 intravenous doses of diclofenac, typical enteropathy was developed with severe enteropathy occurred in distal small intestine. Co-administration of ciprofloxacin significantly alleviated diclofenac-induced enteropathy. Conclusion: Co-administration of ciprofloxacin attenuated enterohepatic circulation of diclofenac and alleviated diclofenac-induced enteropathy in rats, partly via the inhibition of intestinal β-glucuronidase activity.

Therapeutic significance of β-glucuronidase activity and its inhibitors: A review

“…Moreover, at 100 mg/kg doses, oral treatment with glycyrrhizinic acid or intraperitoneal treatment with 18b-glycyrrhetinic acid, protected the hepatocytes of male Wistar rats against CCl 4 -induced liver injury evident by the significant reduction in AST, ALT and LDH levels compared to CCl 4controls. Intraperitoneal administration of glycyrrhizinic acid also did not provide hepatoprotection akin to tectoridin (43). In addition, structurally similar emodinol (46), isolated from the roots of perennial herb Paeonia Emodi showed stronger E. coli bGLU inhibition in vitro with IC 50 ¼ 63 mM compared to 18b-glycyrrhetinic acid [152].…”

“…Fascinatingly, structurally similar tectorigenin (42), an aglycone metabolite of 7-O-glycoside e tectoridin (43), isolated from the flowers of Pueraria thunbergiana, exhibited better inhibitory potency (IC 50 ¼ 0.30 mg/ml) than its congeners [150]. 50 mg/kg intraperitoneal pre-treatment of male ICR mice with tectorigenin or 100 mg/kg oral administration of tectoridin provided better hepatoprotection than dimethyl diphenyl bicarboxylate (DDB) and daidzein, by significantly lowering serum AST, ALT and LDH levels relative to CCl 4 -treated controls.…”

“…Nonetheless, enterobacterial bGLU deconjugation of drug and xenobiotic glucuronides in the gastrointestinal (GI) tract has been implicated in colonic genotoxicity [41] and certain drug-induceddose-limiting toxicities. For example, the GI toxicity of anticancer drug Irinotecan (CPT-11) [42], enteropathy of non-steroidal antiinflammatory drug (NSAID) Diclofenac [43], tissue inflammation and hepatoxicity. Furthermore, bGLU is deemed a potential molecular target for;…”

Short-chain fatty acids oppositely altered expressions and functions of intestinal cytochrome P4503A and P-glycoprotein and affected pharmacokinetics of verapamil following oral administration to rats

“…Several studies have indicated that the opposite regulation seemed to be associated with NF-jB pathways activation. [20,[32][33][34][35][36][37][38][39][40] Reports have showed that SCFAs such as butyrate suppresses NF-kappa B activation [32][33][34] via inhibiting deacetylases. Activation of NF-Kappa B has been reported to be associated with induction of P-gp expression.…”

“…[35][36][37][38] On the contrary, activation of NF-Kappa B has been reported to inhibit expression of Cyp3a. [20,39,40] However, the real mechanisms should be further investigated. Theoretically, the SCFA-induced upregulation of intestinal Cyp3a activity enhanced verapamil metabolism and decreased oral plasma exposure of verapamil.…”