Abstract

BACKGROUND AND PURPOSE
The aim of this study was to obtain evidence for the activation of the nucleoside reverse transcriptase inhibitor abacavir to reactive aldehyde metabolites in vivo. Protein haptenation by these reactive metabolites may be a factor in abacavir-induced toxic events.
EXPERIMENTAL APPROACH
The formation of N-terminal valine adducts from the abacavir-derived aldehydes was investigated in the haemoglobin of Wistar rats treated with eight daily doses (120 mg·kg(-1)) of abacavir. The analyses were conducted by high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry upon comparison with synthetic standards.
KEY RESULTS
An N-terminal valine haemoglobin adduct derived from an α,β-unsaturated aldehyde metabolite of abacavir was identified in vivo for the first time.
CONCLUSIONS AND IMPLICATIONS
This preliminary work on abacavir metabolism provides the first unequivocal evidence for the formation of an α,β-unsaturated aldehyde metabolite in vivo and of its ability to form haptens with proteins. The methodology described herein can be used to assess the formation of this metabolite in human samples and has the potential to become a valuable pharmacological tool for mechanistic studies of abacavir toxicity. In fact, the simplicity of the method suggests that the abacavir adduct with the N-terminal valine of haemoglobin could be used to investigate abacavir-induced toxicity for accurate risk/benefit estimations.

Links

Publisher Full Text

Authors

Charneira C, Grilo NM, Pereira SA, Godinho AL, Monteiro EC, Marques MM, Antunes AM

Institution

Centro de Química Estrutural, Instituto Superior Técnico, Universidade Técnica de Lisboa, Lisboa, Portugal.

Source

British journal of pharmacology 167:6 2012 Nov pg 1353-61

MeSH

Aldehydes
Animals
Anti-HIV Agents
Dideoxynucleosides
Female
Haptens
Hemoglobins
Male
Rats
Rats, Wistar
Serum Albumin
Valine

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22725138