Mechanism of Indinavir-Induced Hyperbilirubinemia

• Published in: Proceedings of the National Academy of Sciences - PNAS 2001-10, Vol.98 (22), p.12671-12676
• Main Authors: Zucker, Stephen D., Qin, Xiaofa, Rouster, Susan D., Yu, Fei, Green, Richard M., Keshavan, Pavitra, Feinberg, Judith, Sherman, Kenneth E.
• Format: Article
• Language: English
• Subjects: Alleles; Animals; antiretroviral therapy; Bilirubin - metabolism; bilirubin UDP-glucuronosyltransferase; Biological Sciences; Blood; Blood plasma; Carcinoma, Hepatocellular - enzymology; Drug therapy; Enzymes; Exons; Genotypes; Glucuronides; Glucuronosyltransferase - metabolism; HIV; HIV Infections - drug therapy; HIV Protease Inhibitors - adverse effects; Human immunodeficiency virus; Hyperbilirubinemia; Hyperbilirubinemia - chemically induced; Indinavir - adverse effects; Liver; Male; Medical research; Rats; Rats, Gunn; Rats, Wistar
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.231140698

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 ≈10% of the population manifesting Gilbert's syndrome. This hypothesis was tested in vitro, 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 (KI= 183 µM) 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 KI(360 µM) 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.