PT - JOURNAL ARTICLE AU - Hyo-Ji Kim AU - Eun Sook Jeong AU - Kyung-Ah Seo AU - Kye Jung Shin AU - Yeon Jae Choi AU - Su-Jun Lee AU - Jong Lyul Ghim AU - Dong-Ryul Sohn AU - Jae-Gook Shin AU - Dong-Hyun Kim TI - Glucuronidation of a Sarpogrelate Active Metabolite Is Mediated by UDP-Glucuronosyltransferases 1A4, 1A9, and 2B4 AID - 10.1124/dmd.113.051862 DP - 2013 Aug 01 TA - Drug Metabolism and Disposition PG - 1529--1537 VI - 41 IP - 8 4099 - http://dmd.aspetjournals.org/content/41/8/1529.short 4100 - http://dmd.aspetjournals.org/content/41/8/1529.full SO - Drug Metab Dispos2013 Aug 01; 41 AB - Sarpogrelate is a selective serotonin 5-HT2A–receptor antagonist used to treat patients with peripheral arterial disease. This drug is rapidly hydrolyzed to its main metabolite (R,S)-1-[2-[2-(3–methoxyphenyl)ethyl]phenoxy]-3-(dimethylamino)-2-propanol (M-1), which is mainly excreted as a glucuronide conjugate. Sarpogrelate was also directly glucuronidated to an O-acyl glucuronide and a N-glucuronide by UDP-glucuronosyltransferases (UGTs) in human liver microsomes (HLMs). Since M-1 is pharmacologically more active than sarpogrelate, we examined glucuronidation of this metabolite in HLMs and characterized the UGTs responsible for M-1 glucuronidation. Diastereomers of O-glucuronide (SMG1 and SMG3) and a N-glucuronide (SMG2) were identified by incubation of M-1 with HLMs in the presence of uridine 5′-diphosphoglucuronic acid (UDPGA), and their structures were confirmed by nuclear magnetic resonance and mass spectrometry analyses. Two O-glucuronides were identified as chiral isomers: SMG1 as R-isomer and SMG3 as S-isomer. Using recombinant UGT enzymes, we determined that SMG1 and SMG3 were predominantly catalyzed by UGT1A9 and UGT2B4, respectively, whereas SMG2 was generated by UGT1A4. In addition, significant correlations were noted between the SMG1 formation rate and propofol glucuronidation (a marker reaction of UGT1A9; r = 0.6269, P < 0.0031), and between the SMG2 formation rate and trifluoperazine glucuronidation (a marker reaction of UGT1A4; r = 0.6623, P < 0.0015) in a panel of HLMs. Inhibition of SMG1, SMG2, and SMG3 formation by niflumic acid, hecogenin, and fluconazole further substantiated the involvement of UGT1A9, UGT1A4, and UGT2B4, respectively. These findings collectively indicate that UGT1A4, UGT1A9, and UGT2B4 are the major UGT isoforms responsible for glucuronidation of M-1, an active metabolite of sarpogrelate.