PT - JOURNAL ARTICLE AU - Ana I. Loureiro AU - Carlos Fernandes-Lopes AU - Maria Joao Bonifacio AU - Lyndon C. Wright AU - Patricio Soares-da-Silva TI - Hepatic UDP-glucuronosyltransferase responsible for eslicarbazepine glucuronidation AID - 10.1124/dmd.111.038620 DP - 2011 Jun 14 TA - Drug Metabolism and Disposition PG - dmd.111.038620 4099 - http://dmd.aspetjournals.org/content/early/2011/06/14/dmd.111.038620.short 4100 - http://dmd.aspetjournals.org/content/early/2011/06/14/dmd.111.038620.full AB - Eslicarbazepine acetate (ESL) is a once-daily novel antiepileptic drug approved in Europe for use as adjunctive therapy for refractory partial-onset seizures with or without secondary generalisation. Metabolism of ESL consists primarily of hydrolysis to eslicarbazepine, which is then subject to glucuronidation followed by renal excretion. In the current study, we have identified that human liver microsomes (HLM) enriched with uridine 5'-diphosphoglucuronic acid (UDPGA) give origin to a single Escherichia coli ß-glucuronidase sensitive eslicarbazepine glucuronide (most likely the O-glucuronide). The kinetics of eslicarbazepine glucuronidation in HLM was investigated in the presence and in the absence of bovine serum albumin (BSA). The apparent Km were 412.2 ± 63.8 µM and 349.7 ±74.3 µM in the presence and absence of BSA, respectively. Incubations with recombinant human uridinediphosphateglucuronosyltransferases (UGTs) indicated that UGT1A4, UGT1A9, UGT2B4, UGT2B7 and UGT2B17 appear to be involved in eslicarbazepine conjugation. The UGT with highest affinity for conjugation was UGT2B4 (Km = 157.0 ± 31.2 µM and 28.7 ± 10.1 µM, in the absence and presence of BSA, respectively). There was a significant correlation between eslicarbazepine glucuronidation and trifluoperazine glucuronidation, a typical UGT1A4 substrate; however, no correlation was found with typical substrates for UGT1A1 and UGT1A9. Diclofenac inhibited eslicarbazepine glucuronidation in HLMs with an IC50 value of 17 µM. In conclusion, glucuronidation of eslicarbazepine results from the contribution of UGT1A4, UGT1A9, UGT2B4, UGT2B7 and UGT2B17, but the high affinity component of UGT2B4 isozyme may play a major role at therapeutic plasma concentrations of unbound eslicarbazepine.