Development of an Early-Warning Model for Predicting the Capecitabine-Induced Diarrhea.

OBJECTIVE

Diarrhea is primary adverse effect of capecitabine (Cap) causing treatment discontinuation. The aim of this study was to construct an early-warning model for predicting the Cap-induced diarrhea.

METHODS

A Cap-induced diarrhea model in mice was constructed in 36 mice, and the exposure levels of Cap and its five metabolites were quantified in plasma and colon and correlated their exposure levels to the diarrhea. The concentrations of metabolic enzymes and drug transporters were quantified in the colon of 62 colorectal cancer (CRC) patients, and an early-warning model was constructed using binary logistic regression.

RESULTS

Totally, 15 out of 36 mice were identified as diarrhea mice, and the exposure levels of Cap and metabolites did not show any differences between diarrhea and non-diarrhea mice in plasma, but in colon, the Cap and metabolites, except for dihydrofluorouracil and 5-fluoro-2'-deoxyuridine, presented significantly higher exposure levels in diarrhea mice. Furthermore, the expression levels of metabolic enzymes and drug transporters in the colon differed distinctly between diarrhea and non-diarrhea CRC patients. Finally, a binary logistic model based on cytidine deaminase (CDA) and solute carrier family 22 member 7 (SLC22A7) was constructed for early-warning of diarrhea induced by Cap: Y = 0.028 × CDA (pg/mL) - 0.518 × SLC22A7 (pg/mL) + 1.526, with the area under curve of 0.907 (specificity 100.0%, sensitivity 71.4%) for diarrhea CRC patients.

CONCLUSION

This study constructed and validated, for the first time, an early-warning model of diarrhea caused by Cap based on metabolic enzymes and drug transporters in normal colon tissue, which may provide a new basis for accurate medication for CRC treatment in clinical practice.