{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,17]],"date-time":"2026-01-17T23:18:11Z","timestamp":1768691891686,"version":"3.49.0"},"reference-count":47,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2022,1,1]],"date-time":"2022-01-01T00:00:00Z","timestamp":1640995200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,1,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Objectives<\/jats:title>\n                  <jats:p>Acetaminophen (APAP) (paracetamol) is a widely used non-prescription drug for pain relief and antipyretic effects. The clearance of APAP is mainly through phase-2 biotransformation catalysed by UDP-glucuronosyl transferases (UGT). Dasabuvir is an anti-hepatitis C drug reported to inhibit several UGT isoforms. The study evaluated the in-vitro inhibitory capacity of dasabuvir versus APAP glucuronidation.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Procedures included human liver microsomal incubations with APAP and isoform-selective probe substrates.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Key findings<\/jats:title>\n                  <jats:p>Dasabuvir inhibited APAP metabolism by a reversible, mixed-type (competitive and non-competitive) partial inhibition, with an inhibition constant Ki = 3.4 \u00b5M. The index constant \u2018a\u2019 was 6.7, indicating the relative contribution of competitive and non-competitive inhibition. The enzyme-inhibitor complex was still able to catalyse the reaction by 12% of the control capacity. Dasabuvir produced strong partial inhibition effect of UGT1A1 and UGT1A9 and relatively complete inhibition of UGT1A6.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Consistent with previous reports, dasabuvir inhibits the activity of 3 UGT isoforms associated with APAP metabolism. In-vitro to in-vivo scaling by 2 different approaches showed identical results, predicting an increased AUC of APAP by a factor of 1.3-fold with coadministration of dasabuvir. Until the findings are confirmed in clinical drug interaction studies, APAP dosage should not exceed 3 g per day in dasabuvir-treated patients to avoid potentially hepatotoxic APAP exposures.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/jpp\/rgab144","type":"journal-article","created":{"date-parts":[[2021,9,14]],"date-time":"2021-09-14T19:56:07Z","timestamp":1631649367000},"page":"131-138","source":"Crossref","is-referenced-by-count":4,"title":["Mechanism of dasabuvir inhibition of acetaminophen glucuronidation"],"prefix":"10.1093","volume":"74","author":[{"given":"Qingchen","family":"Zhang","sequence":"first","affiliation":[{"name":"Program in Pharmacology and Drug Development, Tufts University Graduate School of Biomedical Science and School of Medicine , Boston, MA ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Su Xiang","family":"Duan","sequence":"additional","affiliation":[{"name":"Program in Pharmacology and Drug Development, Tufts University Graduate School of Biomedical Science and School of Medicine , Boston, MA ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jerold S","family":"Harmatz","sequence":"additional","affiliation":[{"name":"Program in Pharmacology and Drug Development, Tufts University Graduate School of Biomedical Science and School of Medicine , Boston, MA ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zixuan","family":"Wei","sequence":"additional","affiliation":[{"name":"Program in Pharmacology and Drug Development, Tufts University Graduate School of Biomedical Science and School of Medicine , Boston, MA ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher A","family":"Singleton","sequence":"additional","affiliation":[{"name":"Program in Pharmacology and Drug Development, Tufts University Graduate School of Biomedical Science and School of Medicine , Boston, MA ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4719-6226","authenticated-orcid":false,"given":"David J","family":"Greenblatt","sequence":"additional","affiliation":[{"name":"Program in Pharmacology and Drug Development, Tufts University Graduate School of Biomedical Science and School of Medicine , Boston, MA ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2022,1,1]]},"reference":[{"key":"2024103012162430200_CIT0001","doi-asserted-by":"crossref","first-page":"202","DOI":"10.7326\/0003-4819-87-2-202","article-title":"Acetaminophen","volume":"87","author":"Ameer","year":"1977","journal-title":"Ann Intern Med"},{"key":"2024103012162430200_CIT0002","first-page":"131","article-title":"Acetaminophen-induced hepatotoxicity: a comprehensive update","volume":"4","author":"Yoon","year":"2016","journal-title":"J Clin Transl Hepatol"},{"key":"2024103012162430200_CIT0003","doi-asserted-by":"crossref","first-page":"1076","DOI":"10.1111\/bcp.12644","article-title":"Favipiravir inhibits acetaminophen sulfate formation but minimally affects systemic pharmacokinetics of acetaminophen","volume":"80","author":"Zhao","year":"2015","journal-title":"Br J Clin Pharmacol"},{"key":"2024103012162430200_CIT0004","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1124\/jpet.117.242107","article-title":"Race, gender, and genetic polymorphism contribute to variability in acetaminophen pharmacokinetics, metabolism, and protein-adduct concentrations in healthy African-American and European-American Volunteers","volume":"362","author":"Court","year":"2017","journal-title":"J Pharmacol Exp Ther"},{"key":"2024103012162430200_CIT0005","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1021\/tx050317i","article-title":"Kinetics of acetaminophen glucuronidation by UDP-glucuronosyltransferases 1A1, 1A6, 1A9 and 2B15. 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