Arttu Uoti, Mika Kurkela, Mikko Niemi, Timo Oksanen, Stefan Oswald, Lauri Puustinen, Heidi Kidron, Noora Sjöstedt
{"title":"Efflux and uptake transport and gut microbial reactivation of raloxifene glucuronides","authors":"Arttu Uoti, Mika Kurkela, Mikko Niemi, Timo Oksanen, Stefan Oswald, Lauri Puustinen, Heidi Kidron, Noora Sjöstedt","doi":"10.1111/bcpt.14107","DOIUrl":null,"url":null,"abstract":"<p>Raloxifene has low bioavailability due to extensive glucuronidation in the intestine and the liver, and its pharmacokinetics is associated with high intra- and interindividual variability. Some of this variability could be explained by the enterohepatic recycling of raloxifene, which is driven by transporter-mediated uptake and efflux and gut microbial deglucuronidation of raloxifene glucuronides. These individual processes involved in raloxifene disposition, however, have not been characterized in full detail. In this study, we evaluated the interactions of raloxifene and its three glucuronide metabolites (raloxifene 4′-glucuronide, raloxifene 6-glucuronide and raloxifene 4′,6-diglucuronide) with drug transporters using Sf9 membrane vesicles and HEK293 cells. Additionally, we measured the deglucuronidation of raloxifene glucuronides in human faecal extracts. All raloxifene glucuronides were transported by MRP2 and MRP3, whereas raloxifene monoglucuronides were identified as substrates of OATP1B1, OATP1B3 and OATP2B1. All three raloxifene glucuronides were readily deglucuronidated in the presence of faecal extracts, although with high between-subject variability. The results of this study provide further understanding of the disposition of raloxifene, which can help understand the sources behind the interindividual variability in raloxifene pharmacokinetics.</p>","PeriodicalId":8733,"journal":{"name":"Basic & Clinical Pharmacology & Toxicology","volume":"136 1","pages":""},"PeriodicalIF":2.7000,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bcpt.14107","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Basic & Clinical Pharmacology & Toxicology","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1111/bcpt.14107","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
引用次数: 0
Abstract
Raloxifene has low bioavailability due to extensive glucuronidation in the intestine and the liver, and its pharmacokinetics is associated with high intra- and interindividual variability. Some of this variability could be explained by the enterohepatic recycling of raloxifene, which is driven by transporter-mediated uptake and efflux and gut microbial deglucuronidation of raloxifene glucuronides. These individual processes involved in raloxifene disposition, however, have not been characterized in full detail. In this study, we evaluated the interactions of raloxifene and its three glucuronide metabolites (raloxifene 4′-glucuronide, raloxifene 6-glucuronide and raloxifene 4′,6-diglucuronide) with drug transporters using Sf9 membrane vesicles and HEK293 cells. Additionally, we measured the deglucuronidation of raloxifene glucuronides in human faecal extracts. All raloxifene glucuronides were transported by MRP2 and MRP3, whereas raloxifene monoglucuronides were identified as substrates of OATP1B1, OATP1B3 and OATP2B1. All three raloxifene glucuronides were readily deglucuronidated in the presence of faecal extracts, although with high between-subject variability. The results of this study provide further understanding of the disposition of raloxifene, which can help understand the sources behind the interindividual variability in raloxifene pharmacokinetics.
期刊介绍:
Basic & Clinical Pharmacology and Toxicology is an independent journal, publishing original scientific research in all fields of toxicology, basic and clinical pharmacology. This includes experimental animal pharmacology and toxicology and molecular (-genetic), biochemical and cellular pharmacology and toxicology. It also includes all aspects of clinical pharmacology: pharmacokinetics, pharmacodynamics, therapeutic drug monitoring, drug/drug interactions, pharmacogenetics/-genomics, pharmacoepidemiology, pharmacovigilance, pharmacoeconomics, randomized controlled clinical trials and rational pharmacotherapy. For all compounds used in the studies, the chemical constitution and composition should be known, also for natural compounds.