Drug-Drug Interaction Related with the Clinical Application of Lung Cancer Treatment Drug

Irinotecan is the major clinical drug used to treat lung cancer, and this study aims to investigate the drug-drug interaction (DDI) between irinotecan and flunarizine. In silico docking of flunarizine into UGT1A1 was performed to determine the inhibition of flunarizine on the activity of UGT1A1 which is the major enzyme catalyzing the metabolic elimination of irinotecan. Homolgy modeling of UGT1A1 using UGT71G1 as the template was carried out. Autodock software was used to dock the chemical structure of flunarizine into the activity cavity of UGT1A1. The activity cavity of UGT1A1 was consisted of the following amino acids: His-14, Arg-83, Thr-87, Lys-90, Phe-128, His-148, Ala-149, Leu-150, Ser-193, Leu-213, Gly-283, Ser-284, Met-285, His-347, Ala-348, Gly-349, Ser-350, His-351, Gly-352, Phe-369, Gly-370, Asp-371, and Asn-375. Both hydrogen bonds and hydrophobic interaction contributed to the inhibition mechanism of flunarizine towards UGT1A1. Flunarizine formed one hydrogen bond with Ser-350 with the distance to be 2.9 nm. Flunarizine formed multiple hydrogen bonds with amino acids residues Ser-13, His-14, Thr-87, Phe-128, His-148, Ala-149, Gly-283, Ser-284, Met-285, His-347, Gly-349, Ser-350, His-351, Phe-369, Gly-370, Asp-371, Gln-372, and Asn-375. In conclusion, this study demonstrated the importance of in silico docking method in the finding of drug-drug interaction between flunarizine and irinotecan.