Fecal SN-38 Content as a Surrogate Predictor of Intestinal SN-38 Exposure and Associated Irinotecan-induced Severe Delayed-Onset Diarrhea by a Novel Use of the Spectrofluorimetric Method

Background

Irinotecan administration can lead to severe delayed-onset diarrhea (SDOD) in clinical practice. Currently, there is no reliable surrogate predictor of intestinal exposure to SN-38 and subsequent diarrhea incidence.

Methods

The relationship between fecal 7-ethyl-10-hydroxycamptothecin (SN-38) content and SDOD was investigated in Fisher 344 rats using a novel spectrofluorimetric method. Additionally, a pharmacokinetic study of irinotecan was performed to evaluate the biodistribution of SN-38 to establish the relationship between tissue and fecal SN-38 exposure.

Results

The spectrofluorimetric method was successfully employed to measure fecal SN-38 and CPT-11 content from Day 3 to Day 6 post-irinotecan administration. Only fecal SN-38 content on Day 3 exhibited a significantly positive correlation with SDOD incidence on Days 4 and 5. A cutoff value of SN-38 ≥ 0.066 mg/g in feces was identified, predicting severe diarrhea incidence with 81% accuracy and 80% specificity. The positive correlation between fecal SN-38 content and SN-38 exposure in the ileum on Day 3 was also reflected in the changes of indicators during intestinal injury, such as prostaglandin E2 level and antioxidant activity.

Conclusion

Fecal SN-38 content proves to be representative of intestinal exposure to SN-38, indicative of intestinal injury, and predictive of SDOD incidence in rats, while the spectrofluorimetric method demonstrates the translational potential.

Graphical Abstract

Fecal SN-38 content as a surrogate predictor for SN-38 intestinal tissue exposure and irinotecan-induced severe delayed-onset diarrhea

The intestinal SN-38 exposure, involving both the distribution of SN-38 from the blood vessel and the reabsorption of SN-38 from intestinal lumen, was shown to be closely related to irinotecan-induced diarrhea. However, intestinal SN-38 exposure is hard to measure in humans. Fecal SN-38 content could serve as a surrogate predictor of intestinal SN-38 exposure, which is dependent on biliary excretion, intestinal excretion to intestinal lumen and bacteria β-glucuronidase activities that convert SN-38G to SN-38.