The Role of Uptake and Efflux Transporters in the Disposition of Glucuronide and Sulfate Conjugates
Glucuronidation and sulfation are the most typical phase II metabolic reactions of drugs. The resulting glucuronide and sulfate conjugates are generally considered inactive and safe. They may, however, be the most prominent drug-related material in the circulation and excreta of humans. The glucuron...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2022-01-01
|
| Series: | Frontiers in Pharmacology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2021.802539/full |
| _version_ | 1798021213484744704 |
|---|---|
| author | Erkka Järvinen Feng Deng Feng Deng Wilma Kiander Alli Sinokki Heidi Kidron Noora Sjöstedt |
| author_facet | Erkka Järvinen Feng Deng Feng Deng Wilma Kiander Alli Sinokki Heidi Kidron Noora Sjöstedt |
| author_sort | Erkka Järvinen |
| collection | DOAJ |
| description | Glucuronidation and sulfation are the most typical phase II metabolic reactions of drugs. The resulting glucuronide and sulfate conjugates are generally considered inactive and safe. They may, however, be the most prominent drug-related material in the circulation and excreta of humans. The glucuronide and sulfate metabolites of drugs typically have limited cell membrane permeability and subsequently, their distribution and excretion from the human body requires transport proteins. Uptake transporters, such as organic anion transporters (OATs and OATPs), mediate the uptake of conjugates into the liver and kidney, while efflux transporters, such as multidrug resistance proteins (MRPs) and breast cancer resistance protein (BCRP), mediate expulsion of conjugates into bile, urine and the intestinal lumen. Understanding the active transport of conjugated drug metabolites is important for predicting the fate of a drug in the body and its safety and efficacy. The aim of this review is to compile the understanding of transporter-mediated disposition of phase II conjugates. We review the literature on hepatic, intestinal and renal uptake transporters participating in the transport of glucuronide and sulfate metabolites of drugs, other xenobiotics and endobiotics. In addition, we provide an update on the involvement of efflux transporters in the disposition of glucuronide and sulfate metabolites. Finally, we discuss the interplay between uptake and efflux transport in the intestine, liver and kidneys as well as the role of transporters in glucuronide and sulfate conjugate toxicity, drug interactions, pharmacogenetics and species differences. |
| first_indexed | 2024-04-11T17:10:10Z |
| format | Article |
| id | doaj.art-38e28bc518434792a428be39698c4846 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-11T17:10:10Z |
| publishDate | 2022-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-38e28bc518434792a428be39698c48462022-12-22T04:12:55ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122022-01-011210.3389/fphar.2021.802539802539The Role of Uptake and Efflux Transporters in the Disposition of Glucuronide and Sulfate ConjugatesErkka Järvinen0Feng Deng1Feng Deng2Wilma Kiander3Alli Sinokki4Heidi Kidron5Noora Sjöstedt6Clinical Pharmacology, Pharmacy, and Environmental Medicine, Department of Public Health, University of Southern Denmark, Odense, DenmarkDepartment of Clinical Pharmacology, Faculty of Medicine, University of Helsinki, Helsinki, FinlandIndividualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Helsinki, FinlandDivision of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, FinlandDivision of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, FinlandDivision of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, FinlandDivision of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, FinlandGlucuronidation and sulfation are the most typical phase II metabolic reactions of drugs. The resulting glucuronide and sulfate conjugates are generally considered inactive and safe. They may, however, be the most prominent drug-related material in the circulation and excreta of humans. The glucuronide and sulfate metabolites of drugs typically have limited cell membrane permeability and subsequently, their distribution and excretion from the human body requires transport proteins. Uptake transporters, such as organic anion transporters (OATs and OATPs), mediate the uptake of conjugates into the liver and kidney, while efflux transporters, such as multidrug resistance proteins (MRPs) and breast cancer resistance protein (BCRP), mediate expulsion of conjugates into bile, urine and the intestinal lumen. Understanding the active transport of conjugated drug metabolites is important for predicting the fate of a drug in the body and its safety and efficacy. The aim of this review is to compile the understanding of transporter-mediated disposition of phase II conjugates. We review the literature on hepatic, intestinal and renal uptake transporters participating in the transport of glucuronide and sulfate metabolites of drugs, other xenobiotics and endobiotics. In addition, we provide an update on the involvement of efflux transporters in the disposition of glucuronide and sulfate metabolites. Finally, we discuss the interplay between uptake and efflux transport in the intestine, liver and kidneys as well as the role of transporters in glucuronide and sulfate conjugate toxicity, drug interactions, pharmacogenetics and species differences.https://www.frontiersin.org/articles/10.3389/fphar.2021.802539/fullABC transporteracyl glucuronidedrug-drug interaction (DDI)enterohepatic recyclingsolute carriersulfotransferase (SULT) |
| spellingShingle | Erkka Järvinen Feng Deng Feng Deng Wilma Kiander Alli Sinokki Heidi Kidron Noora Sjöstedt The Role of Uptake and Efflux Transporters in the Disposition of Glucuronide and Sulfate Conjugates Frontiers in Pharmacology ABC transporter acyl glucuronide drug-drug interaction (DDI) enterohepatic recycling solute carrier sulfotransferase (SULT) |
| title | The Role of Uptake and Efflux Transporters in the Disposition of Glucuronide and Sulfate Conjugates |
| title_full | The Role of Uptake and Efflux Transporters in the Disposition of Glucuronide and Sulfate Conjugates |
| title_fullStr | The Role of Uptake and Efflux Transporters in the Disposition of Glucuronide and Sulfate Conjugates |
| title_full_unstemmed | The Role of Uptake and Efflux Transporters in the Disposition of Glucuronide and Sulfate Conjugates |
| title_short | The Role of Uptake and Efflux Transporters in the Disposition of Glucuronide and Sulfate Conjugates |
| title_sort | role of uptake and efflux transporters in the disposition of glucuronide and sulfate conjugates |
| topic | ABC transporter acyl glucuronide drug-drug interaction (DDI) enterohepatic recycling solute carrier sulfotransferase (SULT) |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2021.802539/full |
| work_keys_str_mv | AT erkkajarvinen theroleofuptakeandeffluxtransportersinthedispositionofglucuronideandsulfateconjugates AT fengdeng theroleofuptakeandeffluxtransportersinthedispositionofglucuronideandsulfateconjugates AT fengdeng theroleofuptakeandeffluxtransportersinthedispositionofglucuronideandsulfateconjugates AT wilmakiander theroleofuptakeandeffluxtransportersinthedispositionofglucuronideandsulfateconjugates AT allisinokki theroleofuptakeandeffluxtransportersinthedispositionofglucuronideandsulfateconjugates AT heidikidron theroleofuptakeandeffluxtransportersinthedispositionofglucuronideandsulfateconjugates AT noorasjostedt theroleofuptakeandeffluxtransportersinthedispositionofglucuronideandsulfateconjugates AT erkkajarvinen roleofuptakeandeffluxtransportersinthedispositionofglucuronideandsulfateconjugates AT fengdeng roleofuptakeandeffluxtransportersinthedispositionofglucuronideandsulfateconjugates AT fengdeng roleofuptakeandeffluxtransportersinthedispositionofglucuronideandsulfateconjugates AT wilmakiander roleofuptakeandeffluxtransportersinthedispositionofglucuronideandsulfateconjugates AT allisinokki roleofuptakeandeffluxtransportersinthedispositionofglucuronideandsulfateconjugates AT heidikidron roleofuptakeandeffluxtransportersinthedispositionofglucuronideandsulfateconjugates AT noorasjostedt roleofuptakeandeffluxtransportersinthedispositionofglucuronideandsulfateconjugates |