Ovarian Cancer Treatment Drug Everolimus Inhibits the Metabolic Elimination of First-Line Anti-Colon Cancer Irinotecan

Ovarian cancer remains to the top severe disease to threaten the health of women, and everolimus is the drug clinically used to treat ovarian cancer. Due to the high frequency of colon cancer resulted from the cancer metastasis, irinotecan might be co-administered with everolimus. This study aims to determine the drug-drug interaction (DDI) between everolimus and irinotecan. In silico docking method was employed to dock everolimus into the activity cavity of UDP-glucuronosyltransferase (UGT) 1A1 which catalyzes the glucuronidation of irinotecan's active metabolite SN-38. The chemical structure of everolimus was drawn, and homology modeling was used to construct the crystal structure of UGT1A1. The activity cavity of UGT1A1 binding with everolimus was consisted of the following amino acids residues: Asp11, Gly12, Ser13, Trp15, Leu16, Ser40, Leu41, Tyr42, Asp45, Ala47, Phe48, Leu51, Val68, His72, Val74, Phe75, Glu76, Asn77, Asp78, Ser79, Phe80, Leu81, Gln82, Arg83, Ser284, Met285, Val286, Arg311, Thr313, Gly314, Thr315, Lys328, Leu330, and Gln332. The hydrophobic interaction contributes to the strong binding capability of everolimus with the activity cavity of UGT1A1, and the amino acids residues contributing to this hydrophobic interaction contained Asp11, Gly-12, Leu41, Tyr42, Asp45, Val68, Glu76, Leu81, Arg83, Ser284, Gly314, Thr315, and Lys328. In conclusion, everolimus-irinotecan interaction might occur during the treatment of ovarian cancer with co-administration of everolimus and irinotecan.