title: Pharmacometabonomic characterization of xenobiotic and endogenous metabolic phenotypes that account for inter-individual variation in isoniazid-induced toxicological response.
abstract: An NMR-based pharmacometabonomic approach was applied to investigate inter-animal variation in response to isoniazid (INH; 200 and 400 mg/kg) in male Sprague-Dawley rats, alongside complementary clinical chemistry and histopathological analysis. Marked inter-animal variability in central nervous system (CNS) toxicity was identified following administration of a high dose of INH, which enabled characterization of CNS responders and CNS non-responders. High-resolution post-dose urinary ¹H NMR spectra were modeled both by their xenobiotic and endogenous metabolic information sets, enabling simultaneous identification of the differential metabolic fate of INH and its associated endogenous metabolic consequences in CNS responders and CNS non-responders. A characteristic xenobiotic metabolic profile was observed for CNS responders, which revealed higher urinary levels of pyruvate isonicotinylhydrazone and β-glucosyl isonicotinylhydrazide and lower levels of acetylisoniazid compared to CNS non-responders. This suggested that the capacity for acetylation of INH was lower in CNS responders, leading to increased metabolism via conjugation with pyruvate and glucose. In addition, the endogenous metabolic profile of CNS responders revealed higher urinary levels of lactate and glucose, in comparison to CNS non-responders. Pharmacometabonomic analysis of the pre-dose ¹H NMR urinary spectra identified a metabolic signature that correlated with the development of INH-induced adverse CNS effects and may represent a means of predicting adverse events and acetylation capacity when challenged with high dose INH. Given the widespread use of INH for the treatment of tuberculosis, this pharmacometabonomic screening approach may have translational potential for patient stratification to minimize adverse events.
authors.affiliation: Biomolecular Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Sir Alexander Fleming Building, South Kensington, London SW7 2AZ, UK.
authors.forename: Katharine
authors.initials: K
authors.lastname: Cunningham
authors.forename: Sandrine P
authors.initials: SP
authors.lastname: Claus
authors.forename: John C
authors.initials: JC
authors.lastname: Lindon
authors.forename: Elaine
authors.initials: E
authors.lastname: Holmes
authors.forename: Jeremy R
authors.initials: JR
authors.lastname: Everett
authors.forename: Jeremy K
authors.initials: JK
authors.lastname: Nicholson
authors.forename: Muireann
authors.initials: M
authors.lastname: Coen
mesh_terms: D000818:Animals; D007538:Isoniazid / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics* / Q000633:toxicity*; D008297:Male; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D055442:Metabolome / Q000187:drug effects / Q000502:physiology; D055432:Metabolomics / Q000379:methods; D019906:Nuclear Magnetic Resonance, Biomolecular; D010641:Phenotype; D025341:Principal Component Analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D014556:Urine / Q000737:chemistry
chemical_list: D007538:Isoniazid