Intestinal secretion of indoxyl sulfate as a possible compensatory excretion pathway in chronic kidney disease
| Autor: | Masanari Miyamoto, Yuuta Tominaga, Yoshimi Sano, Kentaro Yano, Shota Kashiwagura, Yuta Agatsuma, Kaori Morimoto, Takuo Ogihara, Mikio Tomita, Akira Takahashi, Chihaya Kakinuma |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Male medicine.medical_specialty Cell 030232 urology & nephrology Pharmaceutical Science Excretion Rats Sprague-Dawley 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine In vivo Internal medicine medicine ATP Binding Cassette Transporter Subfamily G Member 2 Animals Humans Pharmacology (medical) Secretion Renal Insufficiency Chronic Pharmacology Lucifer yellow Intestinal Secretions Chemistry Multidrug resistance-associated protein 2 Transporter General Medicine medicine.disease Multidrug Resistance-Associated Protein 2 Neoplasm Proteins 030104 developmental biology medicine.anatomical_structure Endocrinology Jejunum Caco-2 Cells Multidrug Resistance-Associated Proteins Indican Kidney disease Sodium-Phosphate Cotransporter Proteins Type I |
| Zdroj: | Biopharmaceuticsdrug disposition. 39(7) |
| ISSN: | 1099-081X |
| Popis: | Indoxyl sulfate (IS) is a protein-bound uremic toxin that progressively accumulates in plasma during chronic kidney disease (CKD), and its accumulation is associated with the progression of CKD. This study examined the intestinal secretion of IS using in situ single-pass intestinal perfusion in a rat model of renal insufficiency, MRP2- and BCRP-overexpressing Sf9 membrane vesicles, and Caco-2 cell monolayers. An in situ single-pass perfusion study in CKD model rats demonstrated that a small amount of IS is secreted into intestinal lumen after iv administration of IS, and the clearance increased AUC-dependently. An excess amount of IS (3 mm) partially inhibited the MRP2- and BCRP-mediated uptake of specific fluorescent substrates, CDCF and Lucifer yellow, respectively, into the membrane vesicles, although IS was not taken up at a physiological concentration, 10 μm. In the Caco-2 cell monolayers, the IS transport was higher in the absorptive direction than in the secretory direction (p < 0.05). p-Aminohippuric acid (PAH) strongly inhibited IS transport in both directions (absorptive, p = 0.142; secretory, p < 0.01). Given that the blood IS levels are much higher than those in the intestinal lumen, it is possible that this unknown PAH-sensitive system contributes to the intestinal IS secretion. Although in situ inhibition study is needed to confirm that this unknown transporter mediates the in vivo intestinal secretion of IS, we speculate that this unknown active efflux system works as a compensatory excretion pathway for excess organic anions such as IS especially in end-stage renal disease. |
| Databáze: | OpenAIRE |
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