RT Journal Article
SR Electronic
T1 Glucuronidation of Edaravone by Human Liver and Kidney Microsomes: Biphasic Kinetics and Identification of UGT1A9 as the Major UDP-Glucuronosyltransferase Isoform
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 734
OP 741
DO 10.1124/dmd.111.043356
VO 40
IS 4
A1 Liping Ma
A1 Jianguo Sun
A1 Ying Peng
A1 Rong Zhang
A1 Feng Shao
A1 Xiaoling Hu
A1 Jianping Zhu
A1 Xiaojin Wang
A1 Xuefang Cheng
A1 Yinci Zhu
A1 Ping Wan
A1 Dong Feng
A1 Hui Wu
A1 Guangji Wang
YR 2012
UL http://dmd.aspetjournals.org/content/40/4/734.abstract
AB Edaravone was launched in Japan in 2001 and was the first neuroprotectant developed for the treatment of acute cerebral infarction. Edaravone is mainly eliminated as glucuronide conjugate in human urine (approximately 70%), but the mechanism involved in the elimination pathway remains unidentified. We investigated the glucuronidation of edaravone in human liver microsomes (HLM) and human kidney microsomes (HKM) and identified the major hepatic and renal UDP-glucuronosyltransferases (UGTs) involved. As we observed, edaravone glucuronidation in HLM and HKM exhibited biphasic kinetics. The intrinsic clearance of glucuronidation at high-affinity phase (CLint1) and low-affinity phase (CLint2) were 8.4 ± 3.3 and 1.3 ± 0.2 μl · min−1 · mg−1, respectively, for HLM and were 45.3 ± 8.2 and 1.8 ± 0.1 μl · min−1 · mg−1, respectively, for HKM. However, in microsomal incubations contained with 2% bovine serum albumin, CLint1 and CLint2 were 16.4 ± 1.2 and 3.7 ± 0.3 μl · min−1 · mg−1, respectively, for HLM and were 78.5 ± 3.9 and 3.6 ± 0.5 μl · min−1 · mg−1, respectively, for HKM. Screening with 12 recombinant UGTs indicated that eight UGTs (UGT1A1, UGT1A6, UGT1A7, UGT1A8, UGT1A9, UGT1A10, UGT2B7, and UGT2B17) produced a significant amount of glucuronide metabolite. Thus, six UGTs (UGT1A1, UGT1A6, UGT1A7, UGT1A9, UGT2B7, and UGT2B17) expressed in human liver or kidney were selected for kinetic studies. Among them, UGT1A9 exhibited the highest activity (CLint1 = 42.4 ± 9.5 μl · min−1 · mg−1), followed by UGT2B17 (CLint = 3.3 ± 0.4 μl · min−1 · mg−1) and UGT1A7 (CLint = 1.7 ± 0.2 μl · min−1 · mg−1). Inhibition study found that inhibitor of UGT1A9 (propofol) attenuated edaravone glucuronidation in HLM and HKM. In addition, edaravone glucuronidation in a panel of seven HLM was significantly correlated (r = 0.9340, p = 0.0021) with propofol glucuronidation. Results indicated that UGT1A9 was the main UGT isoform involved in edaravone glucuronidation in HLM and HKM.