Glucuronidation of a Sarpogrelate Active Metabolite Is Mediated by UDP-Glucuronosyltransferases 1A4, 1A9, and 2B4

Abstract

Sarpogrelate is a selective serotonin 5-HT 2A -receptor antagonist used to treat patients with peripheral arterial disease. This drug is rapidly hydrolyzed to its main metabolite (R,, which is mainly excreted as a glucuronide conjugate. Sarpogrelate was also directly glucuronidated to an O-acyl glucuronide and a Nglucuronide 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 59-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.

Simultaneous determination of sarpogrelate and its active metabolite in human plasma by liquid chromatography with tandem mass spectrometry and its application to a pharmacokinetic study

“…Although plasma concentrations of M‐1 are <1/10 those of sarpogrelate, pharmacokinetic–pharmacodynamic modeling has shown that M‐1 is a more effective inhibitor of platelet aggregation than sarpogrelate . M‐1 further undergoes glucuronide conjugations to form inactive metabolites via UGT1A4, UGT1A9, and UGT2B4, which are mainly excreted into bile . It is necessary to develop analytical methods for the simultaneous quantification of sarpogrelate and M‐1 in biological fluids considering the efficacy of M‐1, polymorphisms of uridine diphosphate‐glucuronosyltransferases, or the drug–drug interactions related to uridine diphosphate‐glucuronosyltransferases.…”

Selective Inhibition of Cytochrome P450 2D6 by Sarpogrelate and Its Active Metabolite, M-1, in Human Liver Microsomes

“…The active metabolite, M-1, reaches a C max of 49.3 ng/mL at 0.9 hour and exhibits slower elimination than sarpogrelate, with a half-life of 4.4 hours (Kim et al, 2013a). After absorption, sarpogrelate and M-1 further undergo glucuronide conjugations to form several metabolites, which are mainly excreted in bile (Kim et al, 2013b). Despite the wide use and excellent pharmacological properties of sarpogrelate, to date there is no information regarding the potential inhibitory effects of sarpogrelate and M-1 on human P450 isozymes.…”

Hepatic Glucuronidation of Isoneochamaejasmin A from the Traditional Chinese MedicineStellera ChamaejasmeL. Root

“…Therefore, INCA can be approximated as a racemate and its 5-/599-, 7-/799-, and 49-/4999-hydroxyl groups are different in spatial configuration to each other. Glucuronide metabolites of some racemates, such as flurbiprofen (Wang et al, 2011), propranolol (Yu et al, 2004(Yu et al, , 2010, propafenone (Xie and Zeng, 2010), and sarpogrelate metabolites (Kim et al, 2013), might be separated on a nonchiral stationary phase column. We believe that M2 also has two constitutional isomers even if they cannot be separated under the present HPLC conditions.…”