Tumor Treatment Drugs-Related Drug-Drug Interaction (DDI) between Vismodegib and Irinotecan

Irinotecan is the first-line anti-tumor drug, and vismodegib is clinical anti-tumor drug for treating recurrent, locally advanced, or metastatic basal cell carcinomas (BCCs). Drug-drug interaction (DDI) potential between irinotecan and vismodegib was investigated in this study, and vismodegib was docked into the activity cavity of UGT1A1 which is the major drug-metabolizing enzyme involved in the metabolic elimination of irinotecan. Homology modeling was used to construct the crystal structure of UGT1A1. The binding study of vismodegib with UGT1A1 demonstrated the strong interaction between vismodegib and UGT1A1. The amino acids residues located in the activity cavity contained Asp11, Gly12, Ser13, His14, Trp15, Asp45, Ala47, Phe48, Gln82, Arg83, Lys90, Ser284, Met285, His347, Gly349, Ser350, and Gln-72. The hydrogen bonds and hydrophobic interaction contributed to the strong inhibition of vismodegib on the activity of UGT1A1. The amino acids residues Ser13, Arg83, Ser350, and Gln372 contributed to the hydrogen bonds interaction. The hydrophobic interaction was formed between vismodegib and the amino acids residues Asp11, Gly12, Trp15, Asp45, Phe48, Gln82, Arg83, Ser284, Met285, His347, and Gly349. In conclusion, vismodegib-irinotecan interaction might exist due to the inhibition of vismodegib towards the UGT1A1-catalyzed elimination of irinotecan.