Practical preclinical model for assessing the potential for unconjugated hyperbilirubinemia produced by human immunodeficiency virus protease inhibitors.

Antimicrobial agents and chemotherapy ·Vol. 50 ·No. 2 ·2006-02-00 ·Pages 762-4

Kempf DJ, Waring JF, Morfitt DC, Werner P, Ebert B, Mitten M, Nguyen B, Randolph JT, DeGoey DA, Klein LL, Marsh K

Abstract

A practical preclinical model for the hyperbilirubinemia produced by human immunodeficiency virus protease inhibitors has been developed. Indinavir and atazanavir produced significant hyperbilirubinemia, whereas amprenavir, the negative control, was indistinguishable from the ritonavir booster dose. This model was used to disqualify an exploratory protease inhibitor from development.

MeSH Terms

Animals Disease Models, Animal HIV Protease Inhibitors/blood,toxicity Hyperbilirubinemia/chemically induced Rats Rats, Gunn

Chemicals

HIV Protease Inhibitors

Authors & Affiliations

11 authors, click to expand affiliations / ORCID

Kempf Dale J

Global Pharmaceutical Research and Development, Abbott, Abbott Park, Illinois 60064, USA. [email protected]

Waring Jeffrey F

Morfitt David C

Werner Paige

Ebert Brian

Mitten Michael

Nguyen Bach

Randolph John T

DeGoey David A

Klein Larry L

Marsh Kennan

References (5)

5 references, click to expand

In vitro inhibition of UDP glucuronosyltransferases by atazanavir and other HIV protease inhibitors and the relationship of this property to in vivo bilirubin glucuronidation.
Drug Metab Dispos. 2005 Nov;33(11):1729-39 PMID: 16118329
Mechanism of indinavir-induced hyperbilirubinemia.
Proc Natl Acad Sci U S A. 2001 Oct 23;98(22):12671-6 PMID: 11606755
Inhibition of human organic anion transporting polypeptide OATP 1B1 as a mechanism of drug-induced hyperbilirubinemia.
Chem Biol Interact. 2004 Nov 20;150(2):179-87 PMID: 15535988
Pharmacokinetic enhancement of inhibitors of the human immunodeficiency virus protease by coadministration with ritonavir.
Antimicrob Agents Chemother. 1997 Mar;41(3):654-60 PMID: 9056009
The 3-methylcholanthrene-inducible UDP-glucuronosyltransferase deficiency in the hyperbilirubinemic rat (Gunn rat) is caused by a -1 frameshift mutation.
J Biol Chem. 1989 Dec 15;264(35):21302-7 PMID: 2512292

Article Info

Journal

Antimicrobial agents and chemotherapy

Abbr.

Antimicrob Agents Chemother

ISSN

0066-4804

DOI

10.1128/AAC.50.2.762-764.2006

[email protected]

Published

2006-02-00

Pages

762-4

Language

English

Region

United States

NLM ID

0315061

PMCID

PMC1366866

Subset

External Links

PubMed source DOI: 10.1128/AAC.50.2.762-764.2006 PMC Full Text View journal details

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Practical preclinical model for assessing the potential for unconjugated hyperbilirubinemia produced by human immunodeficiency virus protease inhibitors.

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