Metabolism of Trimethoprim to a Reactive Iminoquinone Methide by Activated Human Neutrophils and Hepatic Microsomes

The antibacterial agent, trimethoprim, is normally used synergistically with sulfonamides. Its use is associated with idiosyncratic reactions including liver toxicity and agranulocytosis. In this study, we demonstrated that trimethoprim was oxidized by activated human neutrophils, as well as a combi...

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Published inThe Journal of pharmacology and experimental therapeutics Vol. 291; no. 1; p. 292
Main Authors Lai, W G, Zahid, N, Uetrecht, J P
Format Journal Article
LanguageEnglish
Published United States American Society for Pharmacology and Experimental Therapeutics 01.10.1999
Subjects
Acetylcysteine - pharmacology
Animals
Drug Interactions
Free Radical Scavengers - pharmacology
Humans
Hypochlorous Acid - pharmacology
In Vitro Techniques
Magnetic Resonance Spectroscopy
Male
Microsomes, Liver - metabolism
Neutrophils - drug effects
Neutrophils - metabolism
Oxidation-Reduction
Peroxidase - metabolism
Quinones - metabolism
Rats
Rats, Sprague-Dawley
Trimethoprim - metabolism
Trimethoprim - pharmacology
Tritium
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Summary:The antibacterial agent, trimethoprim, is normally used synergistically with sulfonamides. Its use is associated with idiosyncratic reactions including liver toxicity and agranulocytosis. In this study, we demonstrated that trimethoprim was oxidized by activated human neutrophils, as well as a combination of myeloperoxidase/hydrogen peroxide/chloride or hypochlorous acid, to a reactive pyrimidine iminoquinone methide intermediate with a protonated molecular ion of m / z 289 as detected by mass spectrometry. In the presence of N -acetyl- l -cysteine (NAC), the pyrimidine iminoquinone methide could be trapped as three NAC adducts. The three NAC adducts were separable on HPLC, but showed the same protonated molecular ion of m / z 452. The proton NMR spectrum of the major adduct showed that the NAC group was at the 6 position of the pyrimidine ring. The mass spectra of the two minor NAC adducts indicated that they were the two diastereomers in which NAC was attached to the exo -cyclic prechiral carbon of the pyrimidine iminoquinone methide. Incubation of trimethoprim with isolated hepatic microsomes, both human and rat, in presence of NAC gave the same set of trimethoprim-NAC adducts. We propose that the formation of this pyrimidine iminoquinone methide by both hepatic microsomes and neutrophils may be responsible for trimethoprim-induced idiosyncratic hepatotoxicity and agranulocytosis.
ISSN:0022-3565
1521-0103