Metabolism of irinotecan and its active metabolite SN-38 by intestinal microflora in rats

Abstract

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 ß-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 ß-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.

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“…This step is designed to detoxify the metabolite and facilitate its elimination from the body. The metabolites of irinotecan are excreted mainly in the feces, except for SN38-G, which is excreted with the bile [ 85 ]. In the final step, SN38-G is transported to the intestine, where it can be reactivated by bacterial β-glucuronidase (βG).…”

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“…Irinotecan can be metabolized to its active metabolite (SN-38) in the liver, which is then conjugated with the uridine diphosphate glucuronosyltransferase to form SN-38 glucuronide, its inactive form. SN-38 glucuronide can be de-conjugated by the bacterial β-glucuronidase when it is excreted to the intestinal lumen through bile; afterwards, it is transformed to its active form, SN-38, again in the intestinal tract (Yamamoto et al, 1994). SN-38 accumulation in the intestinal tract will induce mucosal damage, resulting in the delayed onset of diarrhea (Atsumi et al, 1995; Takasuna et al, 1996).…”

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“…15,20−22 Alkalinization of the intestinal environment has also been attempted, in efforts to increase the conversion of lactone-active SN-38 into carboxylate-inactive SN-38 (the two forms are in pHdependent equilibrium) that has a lower intestinal absorption, thereby reducing the cytotoxicity experienced by the intestinal mucosa; however, plasma levels of Irinotecan and SN-38 were significantly decreased and the daily treatment regimen of alkalinized water intake is incommodious over the course of therapy. 11,15,23 More commonly, loperamide has been clinically administered to alleviate SN-38-induced diarrhea. While loperamide serves as a CES2 inhibitor, it also functions as an opioid antidiarrheal drug by targeting μ-opioid receptors to delay gut motility.…”

“…As the principal enzyme required for Irinotecan conversion, CES2 activity has been regarded as a significant prognostic and predictive biomarker of patient response to Irinotecan treatment regimes, including FOLFIRINOX, whereby significant correlations between low intratumoral CES2 activity and increased Irinotecan resistance have been observed. ,, Conversely, patients with high intratumoral CES2 activity were found to have increased sensitivity to Irinotecan treatment, defining these patients as Irinotecan-responsive . Unfortunately, a high production of SN-38 stemming from high levels of CES2 often has detrimental side effects, including life-threatening diarrhea, which serves as the major limitation for the therapeutic usage of Irinotecan. − In particular, the high conversion of Irinotecan to SN-38 increases the accumulated amount of cytotoxic SN-38 in the intestine, leading to off-target damage of the intestinal epithelia, which constitutes the main cause of life-threatening diarrhea. , These relations suggest that modulating CES2 activity presents an opportunity to alter drug metabolism and pharmacokinetics, with the overall goal of improving therapy and patient care by controlling CES2-mediated activation of Irinotecan and diminishing SN-38 levels. In principle, small-molecule inhibitors of CES2 can be used in patients with high CES2 activity levels, reducing CES2 activity to overcome subsequent life-threatening side effects from Irinotecan treatment.…”

“…Perhaps the most straightforward clinical approach is to decrease the maximum concentration ( C max ) of Irinotecan administered; despite this reducing off-target effects, a lowered dose of Irinotecan significantly reduced antitumor efficacy and did not ameliorate severe diarrhea in clinical trials . Attempts to reformulate SN-38 to take on other prodrug or delivery approaches involved complexes with PEG, peptides, and cyclodextrin; however, these still exhibit intestinal toxicity due to the accumulation of SN-38 or are still being explored for clinical efficacy. − Other strategies focused on reducing the intestinal amounts of SN-38 have also been tried in mammalian models, including the administration of antibiotics, β-glucuronidase (GUS) inhibitors, and adsorbents; however, these encompass their own adverse effects or have yet to demonstrate efficacy in clinical trials. ,− Alkalinization of the intestinal environment has also been attempted, in efforts to increase the conversion of lactone-active SN-38 into carboxylate-inactive SN-38 (the two forms are in pH-dependent equilibrium) that has a lower intestinal absorption, thereby reducing the cytotoxicity experienced by the intestinal mucosa; however, plasma levels of Irinotecan and SN-38 were significantly decreased and the daily treatment regimen of alkalinized water intake is incommodious over the course of therapy. ,, More commonly, loperamide has been clinically administered to alleviate SN-38-induced diarrhea. While loperamide serves as a CES2 inhibitor, it also functions as an opioid antidiarrheal drug by targeting μ-opioid receptors to delay gut motility .…”