{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,4]],"date-time":"2026-07-04T01:30:31Z","timestamp":1783128631381,"version":"3.54.6"},"reference-count":55,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2023,4,29]],"date-time":"2023-04-29T00:00:00Z","timestamp":1682726400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2023,7]]},"abstract":"<jats:p>Although the United States and Europe have shifted to the prescription use of oral diclofenac due to several serious incidences of cardiotoxicity, it is one of the most commonly used over\u2010the\u2010counter (OTC) pain medicines in major parts of the world. We elucidated the quantitative and tissue\u2010specific contribution of uridine diphosphate\u2010glucuronosyltransferases 17 (UGT2B17) in diclofenac metabolism and pharmacokinetics (PK). UGT2B17 is one of most deleted genes in humans with the gene deletion frequency ranging from ~\u200920% in White population to 90% in Japanese population. The human intestinal and liver microsomes isolated from the high\u2010UGT2B17 expressing individuals showed 21\u2010 and 4\u2010fold greater rate of diclofenac glucuronide (DG) formation than in the null\u2010UGT2B17 carriers, respectively. The greater contribution of intestinal UGT2B17 was confirmed by a strong correlation (<jats:italic>R<\/jats:italic>\u2009=\u20090.78, <jats:italic>P<\/jats:italic>\u2009&lt;\u20090.001) between UGT2B17 abundance and DG formation in individual intestinal microsomes (<jats:italic>n<\/jats:italic>\u2009=\u200914). However, because UGT2B17 is a minor UGT isoform in the liver, DG formation rate correlated better with the expression of UGT2B7. The proteomics\u2010informed physiologically\u2010based pharmacokinetic (PBPK) model explains the reported higher exposure of diclofenac in women consistent with ~\u20093\u2010fold lower expression of UGT2B17. Similarly, our <jats:italic>in silico<\/jats:italic> predictions also corroborate with the reported higher exposure and lower standard clinical dose of diclofenac in Japanese population. Therefore, variable UGT2B17 mediated metabolism of oral diclofenac is a cause of concern, especially in the developing countries where it is still used as an OTC drug. The ontogeny data of UGTs in human hepatocytes can be utilized in developing PBPK models for predicting PK in the pediatric population.<\/jats:p>","DOI":"10.1002\/cpt.2907","type":"journal-article","created":{"date-parts":[[2023,4,12]],"date-time":"2023-04-12T14:18:44Z","timestamp":1681309124000},"page":"161-172","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Intestinal Metabolism of Diclofenac by Polymorphic <scp>UGT2B17<\/scp> Correlates with its Highly Variable Pharmacokinetics and Safety across Populations"],"prefix":"10.1111","volume":"114","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8537-6047","authenticated-orcid":false,"given":"Deepak","family":"Ahire","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences Washington State University  Spokane Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7805-3522","authenticated-orcid":false,"given":"Scott","family":"Heyward","sequence":"additional","affiliation":[{"name":"BioIVT  Halethorpe Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9090-0912","authenticated-orcid":false,"given":"Bhagwat","family":"Prasad","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences Washington State University  Spokane Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,4,29]]},"reference":[{"key":"e_1_2_9_1_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.118.080952"},{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2008.08.004"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.117.078220"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40265-021-01606-x"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1097\/FPC.0b013e32834a8639"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2018.08.003"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.2012.20"},{"key":"e_1_2_9_8_1","unstructured":"Drug Usage Statistics United States 2013\u20132020<https:\/\/clincalc.com\/DrugStats\/Drugs\/Diclofenac>. Accessed November 22 2022."},{"key":"e_1_2_9_9_1","volume-title":"StatPearls","author":"Alfaro R.A.","year":"2022"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clinthera.2014.04.012"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1517\/14740338.2014.846324"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.k3426"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa050493"},{"key":"e_1_2_9_14_1","unstructured":"Fernandez S.The pain game."},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40801-021-00240-z"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1097\/MD.0000000000019881"},{"key":"e_1_2_9_17_1","unstructured":"Non\u2010steroidal anti\u2010inflammatory drugs and diclofenac reviews<https:\/\/www.tga.gov.au\/news\/safety\u2010alerts\/non\u2010steroidal\u2010anti\u2010inflammatory\u2010drugs\u2010and\u2010diclofenac\u2010reviews>. 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