Effect of UDP-glucuronosyltransferase 1A8 polymorphism on raloxifene glucuronidation

Kokawa, Yuki; Kishi, Naoki; Jinno, Hideto; Tanaka-Kagawa, Toshiko; Narimatsu, Shizuo; Hanioka, Nobumitsu

doi:10.1016/j.ejps.2013.03.001

Cited by 14 publications

(9 citation statements)

References 36 publications

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“…However, the single amino acid change in UGT1A8*2 (A173G) had little impact on glucuronidation function. In contrast, UGT1A8*3 (C277Y) is associated with a dramatic reduction of glucuronidation function, as demonstrated by mycophenolic acid metabolism in transfected HEK-293 and Sf9 cells [98][99][100]. Similar results were also found using raloxifene as the substrate either using transfected Sf9 cells [98] or using human tissue microsomes from UGT1A8*2 and *3 allele carriers [101].…”

Section: Racial Disparity In Udp-glucuronosyltransferases (Ugt) Reactionssupporting

confidence: 61%

“…In contrast, UGT1A8*3 (C277Y) is associated with a dramatic reduction of glucuronidation function, as demonstrated by mycophenolic acid metabolism in transfected HEK-293 and Sf9 cells [98][99][100]. Similar results were also found using raloxifene as the substrate either using transfected Sf9 cells [98] or using human tissue microsomes from UGT1A8*2 and *3 allele carriers [101]. In vivo studies also showed that UGT1A8*2 had limited impact on mycophenolic acid plasma exposure [102,103].…”

Section: Racial Disparity In Udp-glucuronosyltransferases (Ugt) Reactionsmentioning

confidence: 57%

“…For UGT1A8 SNPs, UG1A8*2 and *3, reduced protein expression was demonstrated using transfected Sf9 cells [98]. However, the single amino acid change in UGT1A8*2 (A173G) had little impact on glucuronidation function.…”

Section: Racial Disparity In Udp-glucuronosyltransferases (Ugt) Reactionsmentioning

confidence: 99%

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Racial Disparity in Drug Disposition in the Digestive Tract

Gao

Bell

Zhang

et al. 2021

IJMS

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The major determinants of drug or, al bioavailability are absorption and metabolism in the digestive tract. Genetic variations can cause significant differences in transporter and enzyme protein expression and function. The racial distribution of selected efflux transporter (i.e., Pgp, BCRP, MRP2) and metabolism enzyme (i.e., UGT1A1, UGT1A8) single nucleotide polymorphisms (SNPs) that are highly expressed in the digestive tract are reviewed in this paper with emphasis on the allele frequency and the impact on drug absorption, metabolism, and in vivo drug exposure. Additionally, preclinical and clinical models used to study the impact of transporter/enzyme SNPs on protein expression and function are also reviewed. The results showed that allele frequency of the major drug efflux transporters and the major intestinal metabolic enzymes are highly different in different races, leading to different drug disposition and exposure. The conclusion is that genetic polymorphism is frequently observed in different races and the related protein expression and drug absorption/metabolism function and drug in vivo exposure can be significantly affected, resulting in variations in drug response. Basic research on race-dependent drug absorption/metabolism is expected, and FDA regulations of drug dosing adjustment based on racial disparity are suggested.

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Section: Racial Disparity In Udp-glucuronosyltransferases (Ugt) Reactionssupporting

confidence: 61%

Section: Racial Disparity In Udp-glucuronosyltransferases (Ugt) Reactionsmentioning

confidence: 57%

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Racial Disparity in Drug Disposition in the Digestive Tract

Gao

Bell

Zhang

et al. 2021

IJMS

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“…In addition, UGT1A6 can detoxify the carcinogenic arylamines and aryl hydrocarbons, which plays a key role in preventing the carcinogenesis of these compounds (Bock & Kohle, 2005). UGT1A8 is a key UGT isoform located in gastrointestinal tract, and also plays an important in elimination of some important clinical drugs, including raloxifene (Kokawa et al, 2013) and mycophenolic acid (Mackenzie, 2000). In addition, low activity of UGT1A8 has also reported to have some relationship with increased risk of cancers (Dura et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Regulation profile of phosphatidylcholines (PCs) and lysophosphatidylcholines (LPCs) components towards UDP-glucuronosyltransferases (UGTs) isoforms

Gao

et al. 2014

Xenobiotica

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1.Endogenous compounds have been reported to be the regulators of UDP-glucuronosyltransferases (UGTs) isoforms. This study aims to investigate the regulatory effects of the activity of UGT isoforms by two important lipid components phosphatidylcholine (PC) and lysophosphatidylcholines (LPC) using in vitro incubation system. 2.UGTs supersomes-catalyzed 4-methylumbelliferone (4-MU) glucuronidation was used as the probe reaction to evaluate the inhibition of compounds towards UGT isoforms except UGT1A4, and UGT1A4-catalyzed trifluoperazine (TFP) glucuronidation reaction was utilized to phenotype the activity of UGT1A4. 3.About 50 μM of LPC15:0, LPC16:0, LPC17:0, LPC18:0, LPC18:1 and PC16:0, 2:0 exhibited inhibition towards more than 90% activity of UGT isoforms, and other LPC and PC components showed negligible inhibitory potential towards all the UGT isoforms. UGT1A6 and UGT1A8 were identified to be the most sensitive UGT isoforms susceptible for the inhibition by LPC15:0, LPC16:0, LPC17:0, LPC18:0, LPC18:1 and PC16:0, 2:0, indicating the strong influence of these LPC and PC components towards UGT1A6 and UGT1A8-catalyzed metabolic reaction when the concentrations of these components increased.

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“…UDP-glucuronosyl transferases/UGTs, Sulfotransferases) into conjugates. The main metabolites are raloxifene-6-glucuronide (Ral-6-G), raloxifene-4′-glucuronide (Ral-4′-G), and raloxifene-6sulfate (Ral-6-S) ( Figure 1A) [11,12]. However, the disposi-tion of Ral via the sulfonation pathway was not achieved enough studied [13].…”

Section: Introductionmentioning

confidence: 99%

Development and validation of ultra‐high‐performance liquid chromatography–mass spectrometry method for the determination of raloxifene and its phase II metabolites in plasma: Application to pharmacokinetic studies in rats

Sun

et al. 2020

J of Separation Science

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The aim of this study is to establish a reliable liquid chromatographymass spectrometry method to simultaneously quantitate raloxifene, and its major metabolites, raloxifene-6-glucuronide, raloxifene-4′-glucuronide, and raloxifene-6-sulfate in rat plasma samples for pharmacokinetic studies. The separation of the analytes was achieved on a Waters BEH C 18 column. Water (0.1% formic acid) and acetonitrile were used as the mobile phases for elution. A onestep protein precipitation using a mixture solvent was applied for plasma sample preparation. The method was validated following the FDA guidance. The results showed that the linear range were 1.95-1000 nM for raloxifene-6-glucuronide, and raloxifene-4′-glucuronide, 0.195-100 nM for raloxifene-6-sulfate, and 0.195-200 nM for raloxifene, respectively. The lower limit of quantification was 1.95, 1.95, 0.195, and 0.195 nM for raloxifene-6-glucuronide, raloxifene-4′-glucuronide, raloxifene-6-sulfate, and raloxifene, respectively. Only 20 µl of plasma sample was required since the method is sensitive. The intra-and interday variance is <15% and the accuracy is within 85-115%. The variance of matrix effect and recovery were <15%. The method was successfully applied in a pharmacokinetic study in rats with oral administration of raloxifene.

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Effect of UDP-glucuronosyltransferase 1A8 polymorphism on raloxifene glucuronidation

Cited by 14 publications

References 36 publications

Racial Disparity in Drug Disposition in the Digestive Tract

Racial Disparity in Drug Disposition in the Digestive Tract

Regulation profile of phosphatidylcholines (PCs) and lysophosphatidylcholines (LPCs) components towards UDP-glucuronosyltransferases (UGTs) isoforms

Development and validation of ultra‐high‐performance liquid chromatography–mass spectrometry method for the determination of raloxifene and its phase II metabolites in plasma: Application to pharmacokinetic studies in rats

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