title: Metabolism of irinotecan and its active metabolite SN-38 by intestinal microflora in rats.
abstract: One of the dose-limiting toxicities of irinotecan (CPT-11) is delayed-onset diarrhea, which is the greatest barrier to treatment with CPT-11-containing regimens. CPT-11 is converted to its active metabolite, SN-38, which is conjugated by hepatic uridine diphosphate glucuronosyl transferase to SN-38 glucuronide (SN-38G). SN-38G, once excreted in the intestinal lumen via bile, is extensively deconjugated by bacterial beta-glucuronidase with the regeneration of SN-38 in the intestinal lumen, which may cause diarrhea. However, the metabolism of CPT-11 and its metabolites by intestinal microflora are yet to be reported. This study was carried out to investigate the microbial transformation of CPT-11 and SN-38 using an anaerobic mixed culture of rat cecal microorganisms. No reaction in the mixed cultures was observed when CPT-11 or SN-38 lactone was added to the culture medium. When CPT-11 was added to the culture broth, a significant amount of water-soluble CPT-11 was detected in the spent culture medium. In contrast, only a slight amount of SN-38 was found in the supernatant when SN-38 lactone was added to the broth. A significant quantity of SN-38 was found in the sediment. In conclusion, these results strongly suggest that SN-38 produced from SN-38G by the action of bacterial beta-glucuronidase is rapidly adsorbed by the intestinal bacterial cell walls in the sediment because of the hydrophobic and lipophilic nature of SN-38, and a small amount of SN-38 remains in the intestinal luminal fluid. Thus, we need to reconsider the role of SN-38 in the intestinal lumen in CPT-11-induced late-onset diarrhea.
authors.affiliation: Department of Respiratory Medicine, Kitasato University School of Medicine, Kanagawa, Japan.
authors.forename: Michiko
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Akinobu
authors.initials: A
authors.lastname: Kurita
authors.forename: Takashi
authors.initials: T
authors.lastname: Asahara
authors.forename: Akira
authors.initials: A
authors.lastname: Takakura
authors.forename: Ken
authors.initials: K
authors.lastname: Katono
authors.forename: Maiko
authors.initials: M
authors.lastname: Iwasaki
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Ryuge
authors.forename: Mayuko
authors.initials: M
authors.lastname: Wada
authors.forename: Sayaka
authors.initials: S
authors.lastname: Onoda
authors.forename: Tomoko
authors.initials: T
authors.lastname: Yanaihara
authors.forename: Masanori
authors.initials: M
authors.lastname: Yokoba
authors.forename: Hisashi
authors.initials: H
authors.lastname: Mitsufuji
authors.forename: Yasuto
authors.initials: Y
authors.lastname: Nishii
authors.forename: Tomoya
authors.initials: T
authors.lastname: Fukui
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Masuda
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism*; D001419:Bacteria / Q000378:metabolism*; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000378:metabolism; D003967:Diarrhea / Q000139:chemically induced; D007422:Intestines / Q000382:microbiology*; D000077146:Irinotecan; D008297:Male; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D000077146:Irinotecan; D002166:Camptothecin