title: Effects of nonsteroidal anti-inflammatory drugs on the renal excretion of indoxyl sulfate, a nephro-cardiovascular toxin, in rats.
abstract: Chronic kidney disease (CKD) is a health problem worldwide. Indoxyl sulfate (IS) is a nephro-cardiovascular toxin accumulated in CKD patients and cannot be removed through hemodialysis. The renal excretion of IS was mediated by organic anion transporters (OATs) OAT 1 and OAT 3. Because a number of nonsteroidal anti-inflammatory drugs (NSAIDs) have been reported to inhibit OATs, we hypothesize that NSAIDs might inhibit the renal excretion of IS. Rats were intravenously injected IS with and without diclofenac, ketoprofen or salicylic acid, individually. Blood samples were collected at predetermined time points and the concentrations of IS were determined by HPLC method. The results showed that diclofenac and ketoprofen at 10.0mg/kg significantly decreased the systemic clearance of IS by 71% and 82%, and increased the MRT of IS by 106% and 105%, respectively, whereas salicylic acid did not exhibit significant effects. Cell studies indicated that diclofenac and ketoprofen inhibited the uptake of IS mediated by OAT 1 and OAT 3. In conclusion, diclofenac and ketoprofen inhibited the excretion of IS through inhibition on OAT 1 and OAT 3.
authors.affiliation: Department of Pharmacy, China Medical University Hospital, Taichung, Taiwan, ROC.
authors.forename: Chung-Ping
authors.initials: CP
authors.lastname: Yu
authors.affiliation: Department of Pharmaceutics, Virginia Commonwealth University, Richmond, USA.
authors.forename: Douglas H
authors.initials: DH
authors.lastname: Sweet
authors.affiliation: School of Pharmacy, China Medical University, Taichung, Taiwan, ROC.
authors.forename: Yu-Hsuan
authors.initials: YH
authors.lastname: Peng
authors.affiliation: Department of Pharmacy, China Medical University Hospital, Taichung, Taiwan, ROC; School of Pharmacy, China Medical University, Taichung, Taiwan, ROC.
authors.forename: Yow-Wen
authors.initials: YW
authors.lastname: Hsieh
authors.affiliation: School of Pharmacy, China Medical University, Taichung, Taiwan, ROC.
authors.forename: Pei-Dawn Lee
authors.initials: PL
authors.lastname: Chao
authors.affiliation: Department of Pharmacy, China Medical University Hospital, Taichung, Taiwan, ROC; School of Pharmacy, China Medical University, Taichung, Taiwan, ROC.
authors.forename: Yu-Chi
authors.initials: YC
authors.lastname: Hou
authors.affiliation: School of Pharmacy, China Medical University, Taichung, Taiwan, ROC. Electronic address: splin@mail.cmu.edu.tw.
authors.forename: Shiuan-Pey
authors.initials: SP
authors.lastname: Lin
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D016466:CHO Cells; D002319:Cardiovascular System / Q000187:drug effects*; D002460:Cell Line; D003412:Cricetulus; D004008:Diclofenac / Q000494:pharmacology; D004285:Dogs; D057809:HEK293 Cells; D006801:Humans; D007200:Indican / Q000652:urine*; D007660:Ketoprofen / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D027362:Organic Anion Transport Protein 1 / Q000378:metabolism; D029362:Organic Anion Transporters, Sodium-Independent / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D065667:Renal Elimination / Q000187:drug effects*; D020156:Salicylic Acid / Q000494:pharmacology; D014118:Toxins, Biological / Q000652:urine*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D027362:Organic Anion Transport Protein 1; D029362:Organic Anion Transporters, Sodium-Independent; D014118:Toxins, Biological; D004008:Diclofenac; D007660:Ketoprofen; D007200:Indican; D020156:Salicylic Acid
keywords: Chronic kidney disease; Indoxyl sulfate; NSAIDs; Organic anion transporters; Uremic toxin