Mechanism of indinavir-induced hyperbilirubinemia

Proceedings of the National Academy of Sciences of the United States of America
S D ZuckerK E Sherman

Abstract

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 approximately 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 (K(I) = 183 microM) 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 mutan...Continue Reading

References

Jul 1, 1988·Proceedings of the National Academy of Sciences of the United States of America·N E KohlI S Sigal
Aug 1, 1988·Proceedings of the National Academy of Sciences of the United States of America·J P Tam
Sep 1, 1972·The Biochemical Journal·A F McDonagh, F Assisi
Nov 2, 1995·The New England Journal of Medicine·P J BosmaR P Oude Elferink
Jan 8, 1997·JAMA : the Journal of the American Medical Association·S G DeeksJ O Kahn
Jan 1, 1997·AIDS Clinical Review·S G Deeks, P A Volberding
Jul 8, 1998·Proceedings of the National Academy of Sciences of the United States of America·E BeutlerA Demina
Jun 3, 2000·Annual Review of Pharmacology and Toxicology·R H Tukey, C P Strassburg
Oct 6, 2000·Journal of Hepatology·C P Strassburg, M P Manns
Mar 7, 2001·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·M PersicoJ D Ostrow
Aug 15, 2001·Journal of the American Academy of Child and Adolescent Psychiatry·M Stocks

❮ Previous
Next ❯

Citations

Apr 13, 2006·Current HIV/AIDS Reports·David W Haas
Feb 7, 2002·Journal of Hepatology·Ulrich SpenglerJürgen Kurt Rockstroh
Dec 14, 2002·Journal of Hepatology·Piter Jabik Bosma
Sep 11, 2003·The Lancet Oncology·Cecilia SgadariBarbara Ensoli
Apr 12, 2005·Clinical Gastroenterology and Hepatology : the Official Clinical Practice Journal of the American Gastroenterological Association·Kevin M Korenblat, Paul D Berk
Feb 8, 2006·The Pharmacogenomics Journal·S Rodríguez-NóvoaV Soriano
Apr 10, 2002·Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America·Curtis L CooperJonathan B Angel
May 27, 2003·Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America·J T Siveke, J R Bogner
Feb 27, 2004·Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America·Mark S Sulkowski
Jan 19, 2007·Infection Control and Hospital Epidemiology : the Official Journal of the Society of Hospital Epidemiologists of America·Michael C ThigpenCarolyn M Greene
Jun 14, 2008·The Journal of Infectious Diseases·Mark S Sulkowski
Jun 21, 2003·AIDS Patient Care and STDs·Charles HicksChristine Wanke
May 2, 2003·AIDS Patient Care and STDs·Nuria CaminoVincent Soriano
May 15, 2010·Toxicological Sciences : an Official Journal of the Society of Toxicology·Daniela EnnulatKay S Tatsuoka
Oct 13, 2006·Current Opinion in Gastroenterology·James H Lewis
Jun 23, 2006·Journal of Acquired Immune Deficiency Syndromes : JAIDS·Peter L AndersonCourtney V Fletcher
Dec 20, 2007·AIDS·Vincent SorianoBarbara McGovern
Jan 15, 2008·Current Opinion in Infectious Diseases·Elizabeth J Phillips, Simon A Mallal
Jan 28, 2004·Annual Review of Pharmacology and Toxicology·John O MinersPeter I Mackenzie
Sep 22, 2007·Annual Review of Pharmacology and Toxicology·A Telenti, U M Zanger
Jul 30, 2010·American Journal of Physiology. Regulatory, Integrative and Comparative Physiology·Trinity Vera, David E Stec
Jul 3, 2009·American Journal of Physiology. Regulatory, Integrative and Comparative Physiology·Trinity VeraDavid E Stec
May 18, 2013·AIDS Research and Therapy·Aoife G CotterPatrick Wg Mallon
Dec 12, 2012·Pharmacogenomics and Personalized Medicine·Rebecca Pavlos, Elizabeth J Phillips
Oct 24, 2013·World Journal of Gastroenterology : WJG·Eva Sticova, Milan Jirsa
Jun 15, 2007·Pharmacogenomics·Rubin LubomirovAmalio Telenti
Jun 7, 2006·Pharmacogenomics·Julie FoxAlan Winston
Oct 11, 2007·Pharmacogenomics·Qing MaGene D Morse
Nov 13, 2008·Critical Reviews in Clinical Laboratory Sciences·Christian P StrassburgUrsula Ehmer
Oct 31, 2007·Expert Opinion on Drug Safety·S Hyder Hussaini, Elizabeth A Farrington
Jun 2, 2007·Expert Opinion on Drug Metabolism & Toxicology·Tim R CresseyKulkanya Chokephaibulkit
Jun 23, 2015·Drug Metabolism Reviews·Dyah Aryani PerwitasariBob Wilffert
Dec 2, 2015·Chemical Research in Toxicology·Donna M DambachDolores Diaz

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.