Lloyd Wei Tat Tang, Tino Woon Huai Cheong, Eric Chun Yong Chan
{"title":"非布司他及其主要的酰基葡萄糖醛酸代谢物是有机阴离子转运体的有效抑制剂3:与利伐沙班药物相互作用的意义","authors":"Lloyd Wei Tat Tang, Tino Woon Huai Cheong, Eric Chun Yong Chan","doi":"10.1002/bdd.2310","DOIUrl":null,"url":null,"abstract":"<p>Febuxostat is a second-line xanthine oxidase inhibitor that undergoes extensive hepatic metabolism to yield its major acyl-<i>β</i>-D-glucuronide metabolite (febuxostat AG). It was recently reported that febuxostat inhibited organic anion transporter 3 (OAT3)-mediated uptake of enalaprilat. Here, we investigated the inhibition of febuxostat and febuxostat AG on OAT3 in transfected human embryonic kidney 293 cells. Our transporter inhibition assays confirmed the potent noncompetitive and competitive inhibition of OAT3-mediated estrone-3-sulfate transport by febuxostat and febuxostat AG with corresponding apparent <i>K</i><sub>i</sub> values of 0.55 and 6.11 μM respectively. After accounting for probe substrate-dependency and protein binding effects, mechanistic static modelling with the direct factor Xa anticoagulant rivaroxaban estimated a 1.47-fold increase in its systemic exposure when co-administered with febuxostat based on OAT3 interaction which in turn exacerbates the bleeding risk from baseline for patients with atrial fibrillation by 1.51-fold. Taken together, our results suggested that the concomitant usage of febuxostat with rivaroxaban may potentially culminate in a clinically-significant drug-drug interaction and result in an increased risk of bleeding as a result of its OAT3 inhibition.</p>","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":"43 2","pages":"57-65"},"PeriodicalIF":1.7000,"publicationDate":"2022-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"1","resultStr":"{\"title\":\"Febuxostat and its major acyl glucuronide metabolite are potent inhibitors of organic anion transporter 3: Implications for drug-drug interactions with rivaroxaban\",\"authors\":\"Lloyd Wei Tat Tang, Tino Woon Huai Cheong, Eric Chun Yong Chan\",\"doi\":\"10.1002/bdd.2310\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>Febuxostat is a second-line xanthine oxidase inhibitor that undergoes extensive hepatic metabolism to yield its major acyl-<i>β</i>-D-glucuronide metabolite (febuxostat AG). It was recently reported that febuxostat inhibited organic anion transporter 3 (OAT3)-mediated uptake of enalaprilat. Here, we investigated the inhibition of febuxostat and febuxostat AG on OAT3 in transfected human embryonic kidney 293 cells. Our transporter inhibition assays confirmed the potent noncompetitive and competitive inhibition of OAT3-mediated estrone-3-sulfate transport by febuxostat and febuxostat AG with corresponding apparent <i>K</i><sub>i</sub> values of 0.55 and 6.11 μM respectively. After accounting for probe substrate-dependency and protein binding effects, mechanistic static modelling with the direct factor Xa anticoagulant rivaroxaban estimated a 1.47-fold increase in its systemic exposure when co-administered with febuxostat based on OAT3 interaction which in turn exacerbates the bleeding risk from baseline for patients with atrial fibrillation by 1.51-fold. Taken together, our results suggested that the concomitant usage of febuxostat with rivaroxaban may potentially culminate in a clinically-significant drug-drug interaction and result in an increased risk of bleeding as a result of its OAT3 inhibition.</p>\",\"PeriodicalId\":8865,\"journal\":{\"name\":\"Biopharmaceutics & Drug Disposition\",\"volume\":\"43 2\",\"pages\":\"57-65\"},\"PeriodicalIF\":1.7000,\"publicationDate\":\"2022-01-27\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"1\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Biopharmaceutics & Drug Disposition\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1002/bdd.2310\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"PHARMACOLOGY & PHARMACY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Biopharmaceutics & Drug Disposition","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/bdd.2310","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
Febuxostat and its major acyl glucuronide metabolite are potent inhibitors of organic anion transporter 3: Implications for drug-drug interactions with rivaroxaban
Febuxostat is a second-line xanthine oxidase inhibitor that undergoes extensive hepatic metabolism to yield its major acyl-β-D-glucuronide metabolite (febuxostat AG). It was recently reported that febuxostat inhibited organic anion transporter 3 (OAT3)-mediated uptake of enalaprilat. Here, we investigated the inhibition of febuxostat and febuxostat AG on OAT3 in transfected human embryonic kidney 293 cells. Our transporter inhibition assays confirmed the potent noncompetitive and competitive inhibition of OAT3-mediated estrone-3-sulfate transport by febuxostat and febuxostat AG with corresponding apparent Ki values of 0.55 and 6.11 μM respectively. After accounting for probe substrate-dependency and protein binding effects, mechanistic static modelling with the direct factor Xa anticoagulant rivaroxaban estimated a 1.47-fold increase in its systemic exposure when co-administered with febuxostat based on OAT3 interaction which in turn exacerbates the bleeding risk from baseline for patients with atrial fibrillation by 1.51-fold. Taken together, our results suggested that the concomitant usage of febuxostat with rivaroxaban may potentially culminate in a clinically-significant drug-drug interaction and result in an increased risk of bleeding as a result of its OAT3 inhibition.
期刊介绍:
Biopharmaceutics & Drug Dispositionpublishes original review articles, short communications, and reports in biopharmaceutics, drug disposition, pharmacokinetics and pharmacodynamics, especially those that have a direct relation to the drug discovery/development and the therapeutic use of drugs. These includes:
- animal and human pharmacological studies that focus on therapeutic response. pharmacodynamics, and toxicity related to plasma and tissue concentrations of drugs and their metabolites,
- in vitro and in vivo drug absorption, distribution, metabolism, transport, and excretion studies that facilitate investigations related to the use of drugs in man
- studies on membrane transport and enzymes, including their regulation and the impact of pharmacogenomics on drug absorption and disposition,
- simulation and modeling in drug discovery and development
- theoretical treatises
- includes themed issues and reviews
and exclude manuscripts on
- bioavailability studies reporting only on simple PK parameters such as Cmax, tmax and t1/2 without mechanistic interpretation
- analytical methods