Effects of Probenecid on Hepatic and Renal Disposition of Hexadecanedioate, an Endogenous Substrate of Organic Anion Transporting Polypeptide 1B in Rats. 2021

Azusa Futatsugi, and Yusuke Masuo, and Yukio Kato
Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan.

The aim of the present study was to investigate changes in plasma concentrations and tissue distribution of endogenous substrates of organic anion transporting polypeptide (OATP) 1B, hexadecanedioate (HDA), octadecanedioate (ODA), tetradecanedioate (TDA), and coproporphyrin-III, induced by its weak inhibitor, probenecid (PBD), in rats. PBD increased the plasma concentrations of these four compounds regardless of bile duct cannulation, whereas liver-to-plasma (Kp,liver) and kidney-to-plasma concentration ratios of HDA and TDA were reduced. Similar effects of PBD on plasma concentrations and Kp,liver of HDA, ODA, and TDA were observed in kidney-ligated rats, suggesting a minor contribution of renal disposition to the overall distribution of these three compounds. Tissue uptake clearance of deuterium-labeled HDA (d-HDA) in liver was 16-fold higher than that in kidney, and was reduced by 80% by PBD. This was compatible with inhibition by PBD of d-HDA uptake in isolated rat hepatocytes. Such inhibitory effects of PBD were also observed in the human OATP1B1-mediated uptake of d-HDA. Overall, the disposition of HDA is mainly determined by hepatic OATP-mediated uptake, which is inhibited by PBD. HDA might, thus, be a biomarker for OATPs minimally affected by urinary and biliary elimination in rats.

UI MeSH Term Description Entries
D007668 Kidney Body organ that filters blood for the secretion of URINE and that regulates ion concentrations. Kidneys
D008099 Liver A large lobed glandular organ in the abdomen of vertebrates that is responsible for detoxification, metabolism, synthesis and storage of various substances. Livers
D011339 Probenecid The prototypical uricosuric agent. It inhibits the renal excretion of organic anions and reduces tubular reabsorption of urate. Probenecid has also been used to treat patients with renal impairment, and, because it reduces the renal tubular excretion of other drugs, has been used as an adjunct to antibacterial therapy. Benecid,Benemid,Benuryl,Pro-Cid,Probecid,Probenecid Weimer
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D001692 Biological Transport The movement of materials (including biochemical substances and drugs) through a biological system at the cellular level. The transport can be across cell membranes and epithelial layers. It also can occur within intracellular compartments and extracellular compartments. Transport, Biological,Biologic Transport,Transport, Biologic
D051381 Rats The common name for the genus Rattus. Rattus,Rats, Laboratory,Rats, Norway,Rattus norvegicus,Laboratory Rat,Laboratory Rats,Norway Rat,Norway Rats,Rat,Rat, Laboratory,Rat, Norway,norvegicus, Rattus
D022781 Hepatocytes The main structural component of the LIVER. They are specialized EPITHELIAL CELLS that are organized into interconnected plates called lobules. Hepatic Cells,Cell, Hepatic,Cells, Hepatic,Hepatic Cell,Hepatocyte
D027361 Organic Anion Transporters Proteins involved in the transport of organic anions. They play an important role in the elimination of a variety of endogenous substances, xenobiotics and their metabolites from the body. Membrane Transport Proteins, Organic Anion,OAT Transport Protein,OATP Transporter,Organic Anion Transport Polypeptide,Organic Anion Transport Polypeptides,Organic Anion Transport Protein,Organic Anion Transporter,OAT Transport Proteins,OATP Proteins,OATP Transporters,Organic Anion Transport Proteins,Anion Transporter, Organic,Anion Transporters, Organic,Protein, OAT Transport,Transport Protein, OAT,Transport Proteins, OAT,Transporter, OATP,Transporter, Organic Anion,Transporters, OATP,Transporters, Organic Anion
D027381 Liver-Specific Organic Anion Transporter 1 An organic anion transporter found in human and mouse liver. It is capable of transporting a variety organic anions and mediates sodium-independent uptake of bile in the liver. LST-1 Transport Protein,Organic Anion Transport Polypeptide C,Liver-Specific Organic Anion Transporter, LST-1,Oatp-C Transport Protein,SLC21A6 Transporter,Solute Carrier Family-21(Organic Anion Transporter), Member 6 Protein,LST 1 Transport Protein,Liver Specific Organic Anion Transporter 1,Liver Specific Organic Anion Transporter, LST 1,Oatp C Transport Protein,Transport Protein, LST-1,Transport Protein, Oatp-C,Transporter, SLC21A6
D029362 Organic Anion Transporters, Sodium-Independent A subclass of ORGANIC ANION TRANSPORTERS that do not rely directly or indirectly upon sodium ion gradients for the transport of organic ions. Sodium-Independent Organic Anion Transporters,Organic Anion Transporters, Sodium Independent,Sodium Independent Organic Anion Transporters

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