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Toxicol Appl Pharmacol. 2019 Jan 15;363:122-130. doi: 10.1016/j.taap.2018.12.001. Epub 2018 Dec 4.

Metabolome-wide association study of anti-epileptic drug treatment during pregnancy.

Author information

1
Clinical Biomarkers Laboratory, Division of Pulmonary, Allergy, and Critical Care Medicine, Emory University School of Medicine, Atlanta, GA, United States; Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA, United States.
2
Department of Obstetrics-Gynecology, Pennsylvania Hospital, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, United States.
3
Departments of Molecular and Cellular Biology and Medicine, Baylor College of Medicine, Houston, TX, United States.
4
School of Engineering, Brown University, Providence, RI, United States.
5
Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA, United States.
6
The Emmes Corporation, Rockville, MD, United States.
7
Division of Maternal-Fetal Medicine, Department of Obstetrics-Gynecology, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, United States.
8
Department of Neurology, Stanford University, Stanford, CA, United States.
9
Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States.
10
Clinical Biomarkers Laboratory, Division of Pulmonary, Allergy, and Critical Care Medicine, Emory University School of Medicine, Atlanta, GA, United States. Electronic address: dpjones@emory.edu.

Abstract

Pregnant women with epilepsy (PWWE) require continuous anti-epileptic drug (AED) treatment to avoid risk to themselves and fetal risks secondary to maternal seizures, resulting in prolonged AED exposure to the developing embryo and fetus. The objectives of this study were to determine whether high-resolution metabolomics is able to link the metabolite profile of PWWE receiving lamotrigine or levetiracetam for seizure control to associated pharmacodynamic (PD) biological responses. Untargeted metabolomic analysis of plasma obtained from 82 PWWE was completed using high-resolution mass spectrometry. Biological alterations due to lamotrigine or levetiracetam monotherapy were determined by a metabolome-wide association study that compared patients taking either drug to those who did not require AED treatment. Metabolic changes associated with AED use were then evaluated by testing for drug-dose associated metabolic variations and pathway enrichment. AED therapy resulted in drug-associated metabolic profiles recognizable within maternal plasma. Both the parent compounds and major metabolites were detected, and each AED was correlated with other metabolic features and pathways. Changes in metabolites and metabolic pathways important to maternal health and linked to fetal neurodevelopment were detected for both drugs, including changes in one‑carbon metabolism, neurotransmitter biosynthesis and steroid metabolism. In addition, decreased levels of 5-methyltetrahydrofolate and tetrahydrofolate were detected in women taking lamotrigine, which is consistent with recent findings showing increased risk of autism spectrum disorder traits in PWWE using AED. These results represent a first step in development of pharmacometabolomic framework with potential to detect adverse AED-related metabolic changes during pregnancy.

KEYWORDS:

Epilepsy; Folate; High-resolution mass spectrometry; Lamotrigine; Levetiracetam; Pharmacometabolomics

PMID:
30521819
DOI:
10.1016/j.taap.2018.12.001
[Indexed for MEDLINE]

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