title: The Inhibitory Effect of Ciprofloxacin on the β-Glucuronidase-mediated Deconjugation of the Irinotecan Metabolite SN-38-G.
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. 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.
authors.affiliation: Department of Pharmacy, University of Fukui Hospital, Eiheiji-cho, Yoshida-gun, Fukui-ken, Japan.
authors.forename: Takaaki
authors.initials: T
authors.lastname: Kodawara
authors.affiliation: Department of Pharmacy, University of Fukui Hospital, Eiheiji-cho, Yoshida-gun, Fukui-ken, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Higashi
authors.affiliation: Department of Pharmacy, University of Fukui Hospital, Eiheiji-cho, Yoshida-gun, Fukui-ken, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Negoro
authors.affiliation: Department of Pharmacy, University of Fukui Hospital, Eiheiji-cho, Yoshida-gun, Fukui-ken, Japan.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Kamitani
authors.affiliation: Department of Pharmacy, University of Fukui Hospital, Eiheiji-cho, Yoshida-gun, Fukui-ken, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Igarashi
authors.affiliation: Department of Pharmacy, University of Fukui Hospital, Eiheiji-cho, Yoshida-gun, Fukui-ken, Japan.
authors.forename: Kyohei
authors.initials: K
authors.lastname: Watanabe
authors.affiliation: Department of Pharmacy, University of Fukui Hospital, Eiheiji-cho, Yoshida-gun, Fukui-ken, Japan.|Infection Control and Prevention, University of Fukui Hospital, Eiheiji-cho, Yoshida-gun, Fukui-ken, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Tsukamoto
authors.affiliation: Department of Pharmacy, University of Fukui Hospital, Eiheiji-cho, Yoshida-gun, Fukui-ken, Japan.
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Yano
authors.affiliation: Osaka University of Pharmaceutical Sciences, Takatsuki-shi, Osaka-fu, Japan.
authors.forename: Mikio
authors.initials: M
authors.lastname: Masada
authors.affiliation: Department of Pharmacy, University of Fukui Hospital, Eiheiji-cho, Yoshida-gun, Fukui-ken, Japan.|Infection Control and Prevention, University of Fukui Hospital, Eiheiji-cho, Yoshida-gun, Fukui-ken, Japan.
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Iwasaki
authors.affiliation: Department of Pharmacy, University of Fukui Hospital, Eiheiji-cho, Yoshida-gun, Fukui-ken, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Nakamura
mesh_terms: D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D002939:Ciprofloxacin / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004764:Enterohepatic Circulation / Q000187:drug effects; D005966:Glucuronidase / Q000378:metabolism; D020719:Glucuronides / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000077146:Irinotecan; D013997:Time Factors
chemical_list: C441475:7-ethyl-10-hydroxycamptothecin glucuronide; D000900:Anti-Bacterial Agents; D000972:Antineoplastic Agents, Phytogenic; D020719:Glucuronides; D002939:Ciprofloxacin; D000077146:Irinotecan; D005966:Glucuronidase; D002166:Camptothecin