{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,6]],"date-time":"2026-09-06T08:20:00Z","timestamp":1788682800155,"version":"build-2803163510"},"reference-count":33,"publisher":"National Academy of Sciences","issue":"22","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2001,10,23]]},"abstract":"<jats:p>\n                    Indinavir is a viral protease inhibitor used for the treatment of HIV infection. Unconjugated hyperbilirubinemia develops in up to 25% of patients receiving indinavir, prompting drug discontinuation and further clinical evaluation in some instances. We postulated that this side-effect is due to indinavir-mediated impairment of bilirubin UDP-glucuronosyltransferase (UGT) activity and would be most pronounced in individuals with reduced hepatic enzyme levels, as occurs in \u224810% of the population manifesting Gilbert's syndrome. This hypothesis was tested\n                    <jats:italic>in vitro<\/jats:italic>\n                    , in the Gunn rat model of UGT deficiency, and in HIV-infected patients with and without the Gilbert's polymorphism. Indinavir was found to competitively inhibit UGT enzymatic activity (\n                    <jats:italic>K<\/jats:italic>\n                    <jats:sub>I<\/jats:sub>\n                    = 183 \u03bcM) while concomitantly inducing hepatic bilirubin UGT mRNA and protein expression. Although oral indinavir increased plasma bilirubin levels in wild-type and heterozygous Gunn rats, the mean rise was significantly greater in the latter group of animals. Similarly, serum bilirubin increased by a mean of 0.34 mg\/dl in indinavir-treated HIV patients lacking the Gilbert's polymorphism versus 1.45 mg\/dl in those who were either heterozygous or homozygous for the mutant allele. Whereas saquinavir also competitively inhibits UGT activity, this drug has not been associated with hyperbilirubinemia, most likely because of the higher\n                    <jats:italic>K<\/jats:italic>\n                    <jats:sub>I<\/jats:sub>\n                    (360 \u03bcM) and substantially lower therapeutic levels as compared with indinavir. Taken together, these findings indicate that elevations in serum-unconjugated bilirubin associated with indinavir treatment result from direct inhibition of bilirubin-conjugating activity.\n                  <\/jats:p>","DOI":"10.1073\/pnas.231140698","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T10:37:36Z","timestamp":1027679856000},"page":"12671-12676","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":223,"title":["Mechanism of indinavir-induced hyperbilirubinemia"],"prefix":"10.1073","volume":"98","author":[{"given":"Stephen D.","family":"Zucker","sequence":"first","affiliation":[{"name":"Division of Digestive Diseases and Division of Infectious Diseases, University of Cincinnati, Cincinnati, OH 45267; and Division of Gastroenterology and Hepatology, Northwestern University, Chicago, IL 60611"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaofa","family":"Qin","sequence":"additional","affiliation":[{"name":"Division of Digestive Diseases and Division of Infectious Diseases, University of Cincinnati, Cincinnati, OH 45267; 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