Effects of Probenecid on Hepatic and Renal Disposition of Hexadecanedioate,an Endogenous Substrate of Organic Anion Transporting Polypeptide 1B in Rats |
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| Authors: | Azusa Futatsugi Yusuke Masuo Yukio Kato |
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| Affiliation: | Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan |
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| Abstract: | ![]()
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. |
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| Keywords: | Biomarker(s) Organic anion-transporting polypeptide(s) (OATP(s)) Membrane transport Transporter(s) Drug-drug interaction(s) Hepatic transport Organic anion transporter(s) (OAT) Renal transport Inhibition AUC" },{" #name" :" keyword" ," $" :{" id" :" kwrd0060" }," $$" :[{" #name" :" text" ," _" :" area under plasma concentration–time curve area under plasma concentration–time curve from time 0–2 h hepatic concentration at 2 h after administration of rosuvastatin tissue uptake clearance CP-I" },{" #name" :" keyword" ," $" :{" id" :" kwrd0100" }," $$" :[{" #name" :" text" ," _" :" coproporphyrin I CP-III" },{" #name" :" keyword" ," $" :{" id" :" kwrd0110" }," $$" :[{" #name" :" text" ," _" :" coproporphyrin III CsA" },{" #name" :" keyword" ," $" :{" id" :" kwrd0120" }," $$" :[{" #name" :" text" ," _" :" cyclosporin A DDI" },{" #name" :" keyword" ," $" :{" id" :" kwrd0130" }," $$" :[{" #name" :" text" ," _" :" drug-drug interaction d-HDA" },{" #name" :" keyword" ," $" :{" id" :" kwrd0140" }," $$" :[{" #name" :" text" ," _" :" Deuterium-labeled hexadecanedioic acid (1,16-hexadecanedioic-D28 acid) HDA" },{" #name" :" keyword" ," $" :{" id" :" kwrd0150" }," $$" :[{" #name" :" text" ," _" :" hexadecanedioate HEK" },{" #name" :" keyword" ," $" :{" id" :" kwrd0160" }," $$" :[{" #name" :" text" ," _" :" human embryonic kidney HSA" },{" #name" :" keyword" ," $" :{" id" :" kwrd0170" }," $$" :[{" #name" :" text" ," _" :" human serum albumin concentrations required to inhibit transport by 50% KH buffer" },{" #name" :" keyword" ," $" :{" id" :" kwrd0190" }," $$" :[{" #name" :" text" ," _" :" Krebs–Henseleit buffer Michaelis-Menten constant values tissue-to-plasma concentration ratio LC-MS/MS" },{" #name" :" keyword" ," $" :{" id" :" kwrd0220" }," $$" :[{" #name" :" text" ," _" :" liquid chromatography–tandem mass spectrometry MRM" },{" #name" :" keyword" ," $" :{" id" :" kwrd0230" }," $$" :[{" #name" :" text" ," _" :" multiple reaction monitoring OAT" },{" #name" :" keyword" ," $" :{" id" :" kwrd0240" }," $$" :[{" #name" :" text" ," _" :" organic anion transporter OATP" },{" #name" :" keyword" ," $" :{" id" :" kwrd0250" }," $$" :[{" #name" :" text" ," _" :" organic anion–transporting polypeptide ODA" },{" #name" :" keyword" ," $" :{" id" :" kwrd0260" }," $$" :[{" #name" :" text" ," _" :" octadecanedioate PBD" },{" #name" :" keyword" ," $" :{" id" :" kwrd0270" }," $$" :[{" #name" :" text" ," _" :" probenecid PTV" },{" #name" :" keyword" ," $" :{" id" :" kwrd0280" }," $$" :[{" #name" :" text" ," _" :" pitavastatin RIF" },{" #name" :" keyword" ," $" :{" id" :" kwrd0290" }," $$" :[{" #name" :" text" ," _" :" rifampicin RSV" },{" #name" :" keyword" ," $" :{" id" :" kwrd0300" }," $$" :[{" #name" :" text" ," _" :" rosuvastatin TDA" },{" #name" :" keyword" ," $" :{" id" :" kwrd0310" }," $$" :[{" #name" :" text" ," _" :" tetradecanedioate bile efflux velocity from time 1.5–2 h |
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