Ticagrelor Affects the Glucuronidation Metabolism of Anti-Epileptic Drug Carbamazepine in Children

Carbamazepine (CBZ) is is one of the most widely prescribed drugs to treat children epilepsy. UDP-glucuronosyltransferase (UGT) 2B7-catalyzed glucuronidation is the major metabolic elimination pathway of carbamazepine. The present study aims to investigate the inhibition of UGT2B7-catalyzed glucuronidation of CBZ by ticagrelor which is a platelet aggregation inhibitor for preventing thrombotic events. Homology modeling was used to construct the crystal structure of UGT2B7, and in silico docking method was utilized to study the binding capability of ticagrelor with the activity cavity of UGT2B7. The binding free energy of 4-methylumbelliferone (4-MU, probe substrate of UGT2B7) and ticagrelor towards UGT2B7 were -6.04 and -8.36 kcal/mol, respectively, indicating stronger binding ability of ticagrelor than 4-MU for UGT2B7. Therefore, ticagrelor might be a potential inhibitor of UG2B7. Hydrogen bonds and hydrophobic interactions contributed to strong inhibition of ticagrelor on the activity of UGT2B7. This study found that ticagrelor was a new inhibitor of UGT2B7 which is mainly involved in the metabolism of carbamazepine. Therefore, close monitoring of drug-drug interaction between ticagrelor and carbamazepine in the clinic.