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.