title: Glucuronidation of a sarpogrelate active metabolite is mediated by UDP-glucuronosyltransferases 1A4, 1A9, and 2B4.
abstract: 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.
authors.affiliation: Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, #633-165 Gaegum-Dong, Jin-Gu, Busan 614-735, Korea.
authors.forename: Hyo-Ji
authors.initials: HJ
authors.lastname: Kim
authors.forename: Eun Sook
authors.initials: ES
authors.lastname: Jeong
authors.forename: Kyung-Ah
authors.initials: KA
authors.lastname: Seo
authors.forename: Kye Jung
authors.initials: KJ
authors.lastname: Shin
authors.forename: Yeon Jae
authors.initials: YJ
authors.lastname: Choi
authors.forename: Su-Jun
authors.initials: SJ
authors.lastname: Lee
authors.forename: Jong Lyul
authors.initials: JL
authors.lastname: Ghim
authors.forename: Dong-Ryul
authors.initials: DR
authors.lastname: Sohn
authors.forename: Jae-Gook
authors.initials: JG
authors.lastname: Shin
authors.forename: Dong-Hyun
authors.initials: DH
authors.lastname: Kim
mesh_terms: D000818:Animals; D020719:Glucuronides / Q000737:chemistry / Q000378:metabolism*; D014453:Glucuronosyltransferase / Q000502:physiology*; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D051381:Rats; D012702:Serotonin Antagonists / Q000378:metabolism*; D013386:Succinates / Q000378:metabolism*; D000090264:UDP-Glucuronosyltransferase 1A9
chemical_list: D020719:Glucuronides; D012702:Serotonin Antagonists; D013386:Succinates; C000715591:UGT1A9 protein, human; C019787:bilirubin glucuronoside glucuronosyltransferase; C064294:sarpogrelate; D014453:Glucuronosyltransferase; D000090264:UDP-Glucuronosyltransferase 1A9; C486404:UGT2B4 protein, human