{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T03:25:49Z","timestamp":1792121149612,"version":"4.4.0"},"reference-count":61,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2022,5,22]],"date-time":"2022-05-22T00:00:00Z","timestamp":1653177600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2022,9]]},"abstract":"<jats:p>Probenecid is used to treat gout and hyperuricemia as well as increase plasma levels of antiviral drugs and antibiotics. <jats:italic>In vivo<\/jats:italic>, probenecid mainly inhibits the renal SLC22 organic anion transporters OAT1 (SLC22A6), OAT3 (SLC22A8), and URAT1 (SLC22A12). To understand the endogenous role of these transporters in humans, we administered probenecid to 20 healthy participants and metabolically profiled the plasma and urine before and after dosage. Hundreds of metabolites were significantly altered, indicating numerous drug\u2010metabolite interactions. We focused on potential OAT1 substrates by identifying 97 metabolites that were significantly elevated in the plasma and decreased in the urine, indicating OAT\u2010mediated clearance. These included signaling molecules, antioxidants, and gut microbiome products. In contrast, urate was the only metabolite significantly decreased in the plasma and elevated in the urine, consistent with an effect on renal reuptake by URAT1. Additional support comes from metabolomics analyses of our <jats:italic>Oat1<\/jats:italic> and <jats:italic>Oat3<\/jats:italic> knockout mice, where over 50% of the metabolites that were likely OAT substrates in humans were elevated in the serum of the mice. Fifteen of these compounds were elevated in both knockout mice, whereas six were exclusive to the <jats:italic>Oat1<\/jats:italic> knockout and 4 to the <jats:italic>Oat3<\/jats:italic> knockout. These may be endogenous biomarkers of OAT function. We also propose a probenecid stress test to evaluate kidney proximal tubule organic anion transport function in kidney disease. Consistent with the Remote Sensing and Signaling Theory, the profound changes in metabolite levels following probenecid treatment support the view that SLC22 transporters are hubs in the regulation of systemic human metabolism.<\/jats:p>","DOI":"10.1002\/cpt.2630","type":"journal-article","created":{"date-parts":[[2022,5,1]],"date-time":"2022-05-01T16:03:55Z","timestamp":1651421035000},"page":"653-664","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":47,"title":["Blockade of Organic Anion Transport in Humans After Treatment With the Drug Probenecid Leads to Major Metabolic Alterations in Plasma and Urine"],"prefix":"10.1111","volume":"112","author":[{"given":"Jeffry C.","family":"Granados","sequence":"first","affiliation":[{"name":"Department of Bioengineering University of California San Diego  La Jolla California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vibha","family":"Bhatnagar","sequence":"additional","affiliation":[{"name":"Department of Family Medicine University of California San Diego  La Jolla California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanjay K.","family":"Nigam","sequence":"additional","affiliation":[{"name":"Department of Pediatrics University of California San Diego  La Jolla California USA"},{"name":"Department of Medicine University of California San Diego  La Jolla California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,5,22]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12012-011-9145-8"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/438006a"},{"key":"e_1_2_10_4_1","first-page":"35","article-title":"Pharmacology of drugs for hyperuricemia \u2013 mechanisms, kinetics and interactions","volume":"147","author":"Pea E.","year":"2005","journal-title":"Hyperuricemic Syndrom. Pathophysiol. Ther."},{"key":"e_1_2_10_5_1","first-page":"30","article-title":"Efficacy and tolerability of probenecid as urate\u2010lowering therapy in gout; clinical experience in a high prevalence population","volume":"42","author":"Pui K.","year":"2012","journal-title":"Intern. Med. J."},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1097\/MNH.0000000000000427"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI42344"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.2174\/138161205774913219"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41581-019-0174-z"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.3899\/jrheum.121301"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jare.2017.04.008"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.2165\/00003088-198106020-00004"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.272.10.6471"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M116.745216"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M117.796516"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-04949-2"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pharmtox-010617-052713"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA119.010729"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2021.100575"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2012.07.010"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2021.100603"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep34995"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1440-1797.2010.01368.x"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1124\/mol.109.056564"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd4461"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1124\/mol.110.070607"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.1818"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21051791"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms222413407"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-47798-x"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1124\/pr.113.007518"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1080\/17425255.2017.1372425"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jfda.2018.03.002"},{"key":"e_1_2_10_34_1","first-page":"209","article-title":"Treatment of gonorrhoea with a combination of probenecid and procaine penicillin in Rwanda","volume":"5","author":"Meheus A.Z.","year":"1976","journal-title":"Afr. J. Med. Med. Sci."},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00025.2013"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1021\/pr200093w"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00619.2004"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.2215\/CJN.02440314"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.2174\/1389200221666200620210522"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M508050200"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.133817"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2008020180"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.272534"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.113.052647"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2017.00617"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-05470-4"},{"key":"e_1_2_10_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2010.12.004"},{"key":"e_1_2_10_48_1","doi-asserted-by":"publisher","DOI":"10.2174\/1568008054863781"},{"key":"e_1_2_10_49_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep00373"},{"key":"e_1_2_10_50_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaf9794"},{"key":"e_1_2_10_51_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.120.000076"},{"key":"e_1_2_10_52_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.2634"},{"key":"e_1_2_10_53_1","doi-asserted-by":"publisher","DOI":"10.1002\/dta.2727"},{"key":"e_1_2_10_54_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262-021-01004-2"},{"key":"e_1_2_10_55_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.121.000486"},{"key":"e_1_2_10_56_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.118.252643"},{"key":"e_1_2_10_57_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ekir.2021.03.879"},{"key":"e_1_2_10_58_1","doi-asserted-by":"publisher","DOI":"10.2174\/1389200216666150401110610"},{"key":"e_1_2_10_59_1","doi-asserted-by":"publisher","DOI":"10.2174\/1874192401105010049"},{"key":"e_1_2_10_60_1","doi-asserted-by":"publisher","DOI":"10.1002\/pds.1547"},{"key":"e_1_2_10_61_1","first-page":"24","article-title":"Recognizing the risks of chronic nonsteroidal anti\u2010inflammatory drug use in older adults","volume":"18","author":"Marcum Z.A.","year":"2010","journal-title":"Ann. Longterm Care"},{"key":"e_1_2_10_62_1","doi-asserted-by":"publisher","DOI":"10.2215\/CJN.11070821"}],"container-title":["Clinical Pharmacology &amp; Therapeutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpt.2630","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cpt.2630","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpt.2630","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,7]],"date-time":"2023-11-07T13:31:28Z","timestamp":1699363888000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1002\/cpt.2630"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,22]]},"references-count":61,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2022,9]]}},"alternative-id":["10.1002\/cpt.2630"],"URL":"https:\/\/doi.org\/10.1002\/cpt.2630","archive":["Portico"],"relation":{},"ISSN":["0009-9236","1532-6535"],"issn-type":[{"value":"0009-9236","type":"print"},{"value":"1532-6535","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,22]]},"assertion":[{"value":"2022-03-10","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-04-17","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-05-22","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}