Serum NMR metabolomics uncovers multiple metabolic changes in phenobarbital-treated dogs

Abstract

Introduction Phenobarbital is a commonly used anticonvulsant for the treatment of canine epileptic seizures. In addition to its central nervous system (CNS) depressing effects, long-term phenobarbital administration affects liver function. However, broader metabolic consequences of phenobarbital treatment are poorly characterized. Objectives To identify metabolic changes in the sera of phenobarbital-treated dogs and to investigate the relationship between serum phenobarbital concentration and metabolite levels. Methods Leftovers of clinical samples were used: 58 cases with phenobarbital concentrations ranging from 7.8 µg/mL to 50.8 µg/mL, and 25 controls. The study design was cross-sectional. The samples were analyzed by a canine-specific 1H NMR metabolomics platform. Differences between the case and control groups were evaluated by logistic regression. The linear relationship between metabolite and phenobarbital concentrations was evaluated using linear regression. Results Increasing concentrations of glycoprotein acetyls, LDL particle size, palmitic acid, and saturated fatty acids, and decreasing concentrations of albumin, glutamine, histidine, LDL particle concentration, multiple HDL measures, and polyunsaturated fatty acids increased the odds of the sample belonging to the phenobarbital-treated group, having a p-value < .0033, and area under the curve (AUC) > .7. Albumin and glycoprotein acetyls had the best discriminative ability between the groups (AUC: .94). No linear associations between phenobarbital and metabolite concentrations were observed. Conclusion The identified metabolites are known to associate with, for example, liver and CNS function, inflammatory processes and drug binding. The lack of a linear association to phenobarbital concentration suggests that other factors than the blood phenobarbital concentration contribute to the magnitude of metabolic changes.

The effect of phenobarbital treatment on behavioral comorbidities and on the composition and function of the fecal microbiome in dogs with idiopathic epilepsy

“…Due to their being small molecules of fatty acids, they can be rapidly absorbed and transported via circulation to the liver and other organs, namely, the brain, easily crossing the blood–brain barrier (BBB) ( 49 ). In another study, serum saturated fatty acid concentrations in PB-treated dogs were evaluated and were significantly higher than in controls ( 50 ). The beneficial functions of SCFAs are well studied in the intestine but only to a lesser degree in CNS.…”

Metabolic changes associated with two endocrine abnormalities in dogs: elevated fructosamine and low thyroxine

“…GlycA is a composite inflammatory marker elevated in multiple chronic diseases in humans, and is associated with chronic low-grade inflammation, risk of severe infection, diabetes mellitus, and even mortality (Ahola-Olli et al, 2019;Würtz et al, 2017). Until now, it has been scarcely studied in dogs, but elevated concentrations have been observed in dogs with hypo-and hyperadrenocorticism, elevated liver enzyme activities, hyperlipidemia and phenobarbital treatment (Imbery et al, 2022a(Imbery et al, , 2022bOttka et al 2021aOttka et al , 2021b.…”

“…Thus, results of glucose and lactate should be interpreted with caution. However, the use of the leftover samples and comparison with well-established markers is still an excellent, animal-friendly resource for new insights and hypothesis generation (Imbery et al, 2022a(Imbery et al, , 2022bOttka et al, 2021b).…”

“…The control group (n = 25) included samples with all standard clinical chemistry and hematology measures having normal results (Online Resource S2), and were previously used in another study (Ottka et al, 2021b ). The high fructosamine group (n = 80) comprised of samples with serum fructosamine concentration above the reference limit of 374 µmol/l.…”

Metabolomic serum abnormalities in dogs with hepatopathies

“…Normal ranges of serum GlycA concentrations have been assessed by 1 H NMR spectroscopy in dogs 30 and were increased in phenobarbital-treated dogs 97 . In addition, serum α 1 -acid glycoprotein concentrations were elevated in dogs with acute hepatopathies 98 .…”