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

• Published in: Basic & clinical pharmacology & toxicology Vol. 118; no. 5; pp. 333 - 337
• Main Authors: Kodawara, Takaaki, Higashi, Takashi, Negoro, Yutaka, Kamitani, Yukio, Igarashi, Toshiaki, Watanabe, Kyohei, Tsukamoto, Hitoshi, Yano, Ryoichi, Masada, Mikio, Iwasaki, Hiromichi, Nakamura, Toshiaki
• Format: Journal Article
• Language: English
• Published: England 01.05.2016
• Subjects: Anti-Bacterial Agents - administration & dosage; Anti-Bacterial Agents - pharmacology; Antineoplastic Agents, Phytogenic - administration & dosage; Antineoplastic Agents, Phytogenic - pharmacokinetics; Camptothecin - administration & dosage; Camptothecin - analogs & derivatives; Camptothecin - pharmacokinetics; Ciprofloxacin - administration & dosage; Ciprofloxacin - pharmacology; Dose-Response Relationship, Drug; Enterohepatic Circulation - drug effects; Glucuronidase - metabolism; Glucuronides - administration & dosage; Glucuronides - pharmacokinetics; Time Factors
• ISSN: 1742-7835; 1742-7843
• DOI: 10.1111/bcpt.12511

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. β‐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 β‐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 β‐glucuronidase. Ciprofloxacin and phenolphthalein‐β‐d‐glucuronide (PhePG), a typical β‐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 β‐glucuronidase‐mediated conversion of SN‐38‐G to SN‐38 with a half‐maximal inhibitory concentration (IC50) value of 83.8 μM. 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 β‐glucuronidase‐mediated SN‐38‐G deconjugation.