Transporters for Bile Acids and Organic Anions

Suzuki, Hiroshi; Sugiyama, Yuichi

doi:10.1007/0-306-46812-3_14

Cited by 42 publications

(33 citation statements)

References 178 publications

(206 reference statements)

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“…As the basolateral OATPs show overlapping substrate specificity with the canalicular bilirubin conjugate efflux transporter MRP2 (Suzuki and Sugiyama, 1999), it is not surprising that we also find inhibition of MRP2-mediated transport by silibinin. Although MRP2 has been reported to play an important role in the excretion of silibinin conjugates, but not of silibinin itself, in rats (Miranda et al, 2008), data about the interaction of silibinin with efflux transporters, belonging to the ABC family, focused on P-glycoprotein (MDR1) (Zhang and Morris, 2003a,b;Wu et al, 2008), Mrp1 (Nguyen et al, 2003;Łania-Pietrzak et al, 2005;Wu et al, 2005), Mrp4 (Wu et al, 2005), and Mrp5 (Wu et al, 2005).…”

Section: Discussionmentioning

confidence: 62%

Hepatocellular Organic Anion–Transporting Polypeptides (OATPs) and Multidrug Resistance–Associated Protein 2 (MRP2) Are Inhibited by Silibinin

Wlcek

Koller

Ferenci

et al. 2013

Drug Metabolism and Disposition

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Silibinin has been reported to be a promising compound for hepatitis C treatment of nonresponders to standard treatment. Although administered silibinin is well tolerated, increased serum bilirubin levels have been observed during high-dose i.v. silibinin therapy. The mechanism of silibinin-induced hyperbilirubinemia in humans, however, has not been identified so far. The aim of this study was to investigate the effect of silibinin on hepatocellular uptake and efflux transport systems for organic anions to elucidate the cause of silibinin-induced hyperbilirubinemia. Therefore, the effect of silibinin on transport activity of the hepatocellular uptake transporters organic anion-transporting polypeptides (OATPs) OATP1B1, OATP1B3, and OATP2B1, as well as Na + -taurocholate cotransporting polypeptide (NTCP) and of the efflux transporters multidrug resistance-associated protein 2 (MRP2) and bile-salt export pump (BSEP) was studied. The effect of silibinin on OATPs and NTCP function was studied in stable transfected Chinese hamster ovary cells using the radiolabeled model substrates estrone-3-sulfate and dehydroepiandrosteronesulfate for OATPs and taurocholate for NTCP. Interaction of silibinin with MRP2 and BSEP was measured in vesicles isolated from Sf21 or Sf9 insect cells expressing these transporters using either estradiol-17b-glucuronide or taurocholate as substrates. OATP1B1, OATP1B3, and OATP2B1 were inhibited by silibinin, with OATP1B1 being inhibited by (a) complex mechanism(s). An inhibitory effect was also seen for MRP2. In contrast, the bile acid transporters NTCP and BSEP were not affected by silibinin. We concluded that silibinininduced hyperbilirubinemia may be caused by an inhibition of the bilirubin-transporting OATPs and the efflux-transporter MRP2.

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Section: Discussionmentioning

confidence: 62%

Hepatocellular Organic Anion–Transporting Polypeptides (OATPs) and Multidrug Resistance–Associated Protein 2 (MRP2) Are Inhibited by Silibinin

Wlcek

Koller

Ferenci

et al. 2013

Drug Metabolism and Disposition

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“…Many drugs are actively taken up into hepatocytes via specific uptake transporters that include organic anion transporting polypeptide (OATP) 1B1 (SLCO1B1), OATP1B3 (SLCO1B3), and OATP2B1 (SLCO2B1); the organic anion transporter (OAT) 2 (SLC22A7); and the organic cation transporter (OCT) 1 (SLC22A1). ATP binding-cassette (ABC) efflux transporters localized on the canalicular membrane of hepatocytes, such as P-glycoprotein (P-gp) (ABCB1), multidrug resistance-associated protein (MRP) 2 (ABCC2), breast cancer resistance protein (BCRP) (ABCG2), and BSEP (ABCB11), are mainly responsible for canalicular secretion (Ishikawa et al, 1995;Muller and Jansen, 1997;Suzuki and Sugiyama, 1999;Chandra and Brouwer, 2004). Based on the analysis of physicochemical property space, ionization state, size, and polarity were noted to be important determinants in the biliary elimination, and these properties are also closely associated with molecular interaction with the hepatic uptake transporters Varma et al, 2012a) The extended clearance equations (Equations 6 and 7) can be applied to get an estimate of the effect of transporter involvement in the hepatic disposition and further to predict the overall hepatic clearance (Liu and Pang, 2005;Barton et al, 2013).…”

Section: Predicting Clearancementioning

confidence: 99%

A Perspective on the Prediction of Drug Pharmacokinetics and Disposition in Drug Research and Development

Feng

Goosen

et al. 2013

Drug Metabolism and Disposition

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Prediction of human pharmacokinetics of new drugs, as well as other disposition attributes, has become a routine practice in drug research and development. Prior to the 1990s, drug disposition science was used in a mostly descriptive manner in the drug development phase. With the advent of in vitro methods and availability of human-derived reagents for in vitro studies, drugdisposition scientists became engaged in the compound design phase of drug discovery to optimize and predict human disposition properties prior to nomination of candidate compounds into the drug development phase. This has reaped benefits in that the attrition rate of new drug candidates in drug development for reasons of unacceptable pharmacokinetics has greatly decreased. Attributes that are predicted include clearance, volume of distribution, halflife, absorption, and drug-drug interactions. In this article, we offer our experience-based perspectives on the tools and methods of predicting human drug disposition using in vitro and animal data.

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“…ABC transporters are favorite targets of reviewers. A treatise on all known ABC transporters is in the making (11); mammalian ABC transporters have been reviewed as a group (2); and there are numerous recent reviews on subfamilies of transporters (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23) or individual transporters (24 -28, 28a). To avoid unproductive repetition, we focus here on some generalizations that could be useful to people outside this field of research, and on recent developments and controversies.…”

mentioning

confidence: 99%

Mammalian ABC Transporters in Health and Disease

Borst

Elferink

2002

Annu. Rev. Biochem.

1,413

1,152

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f Abstract The ATP-binding cassette (ABC) transporters are a family of large proteins in membranes and are able to transport a variety of compounds through membranes against steep concentration gradients at the cost of ATP hydrolysis. The available outline of the human genome contains 48 ABC genes; 16 of these have a known function and 14 are associated with a defined human disease. Major physiological functions of ABC transporters include the transport of lipids, bile salts, toxic compounds, and peptides for antigen presentation or other purposes. We review the functions of mammalian ABC transporters, emphasizing biochemical mechanisms and genetic defects. Our overview illustrates the importance of ABC transporters in human physiology, toxicology, pharmacology, and disease. We focus on three topics: (a) ABC transporters transporting drugs (xenotoxins) and drug conjugates. (b) Mammalian secretory epithelia using ABC transporters to excrete a large number of substances, sometimes against a steep concentration gradient. Several inborn errors in liver metabolism are due to mutations in one of the genes for these pumps; these are discussed. (c) A rapidly increasing number of ABC transporters are found to play a role in lipid transport. Defects in each of these transporters are involved in human inborn or acquired diseases.

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Transporters for Bile Acids and Organic Anions

Cited by 42 publications

References 178 publications

Hepatocellular Organic Anion–Transporting Polypeptides (OATPs) and Multidrug Resistance–Associated Protein 2 (MRP2) Are Inhibited by Silibinin

Hepatocellular Organic Anion–Transporting Polypeptides (OATPs) and Multidrug Resistance–Associated Protein 2 (MRP2) Are Inhibited by Silibinin

A Perspective on the Prediction of Drug Pharmacokinetics and Disposition in Drug Research and Development

Mammalian ABC Transporters in Health and Disease

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