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Sertraline-induced potentiation of the CYP3A4-dependent neurotoxicity of carbamazepine: an in vitro study.

Publication ,  Journal Article
Ghosh, C; Hossain, M; Spriggs, A; Ghosh, A; Grant, GA; Marchi, N; Perucca, E; Janigro, D
Published in: Epilepsia
March 2015

OBJECTIVE: Drug toxicity is a hurdle to drug development and to clinical translation of basic research. Antiepileptic drugs such as carbamazepine (CBZ) and selective serotonin reuptake inhibitors such as sertraline (SRT) are commonly co-prescribed to patients with epilepsy and comorbid depression. Because SRT may interfere with cytochrome P450 (CYP) enzyme activity and CYPs have been implicated in the conversion of CBZ to reactive cytotoxic metabolites, we investigated in vitro models to determine whether SRT affects the neurotoxic potential of CBZ and the mechanisms involved. METHODS: Human fetal brain-derived dopaminergic neurons, human brain microvascular endothelial cells (HBMECs), and embryonic kidney (HEK) cells were used to evaluate cytotoxicity of CBZ and SRT individually and in combination. Nitrite and glutathione (GSH) levels were measured with drug exposure. To validate the role of CYP3A4 in causing neurotoxicity, drug metabolism was compared to cell death in HEK CYP3A4 overexpressed and cells pretreated with the CYP3A4 inhibitor ketoconazole. RESULTS: In all cellular systems tested, exposure to CBZ (127 μM) or SRT (5 μM) alone caused negligible cytotoxicity. By contrast CBZ, tested at a much lower concentration (17 μM) in combination with SRT (5 μM), produced prominent cytotoxicity within 15 min exposure. In neurons and HBMECs, cytotoxicity was associated with increased nitrite levels, suggesting involvement of free radicals as a pathogenetic mechanism. Pretreatment of HBMECs with reduced GSH or with the GSH precursor N-acetyl-L-cysteine prevented cytotoxic response. In HEK cells, the cytotoxic response to the CBZ + SRT combination correlated with the rate of CBZ biotransformation and production of 2-hydroxy CBZ, further suggesting a causative role of reactive metabolites. In the same system, cytotoxicity was potentiated by overexpression of CYP3A4, and prevented by CYP3A4 inhibitor. SIGNIFICANCE: These results demonstrate an unexpected neurotoxic interaction between CBZ and SRT, apparently related to increased CYP3A4-mediated production of reactive CBZ metabolites. The potential clinical implications of these findings are discussed.

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Published In

Epilepsia

DOI

EISSN

1528-1167

Publication Date

March 2015

Volume

56

Issue

3

Start / End Page

439 / 449

Location

United States

Related Subject Headings

  • Time Factors
  • Sertraline
  • Selective Serotonin Reuptake Inhibitors
  • Nitrites
  • Neurology & Neurosurgery
  • Microsomes, Liver
  • Ketoconazole
  • Humans
  • Glutathione
  • Gene Expression Regulation
 

Citation

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Ghosh, C., Hossain, M., Spriggs, A., Ghosh, A., Grant, G. A., Marchi, N., … Janigro, D. (2015). Sertraline-induced potentiation of the CYP3A4-dependent neurotoxicity of carbamazepine: an in vitro study. Epilepsia, 56(3), 439–449. https://doi.org/10.1111/epi.12923
Ghosh, Chaitali, Mohammad Hossain, Addison Spriggs, Arnab Ghosh, Gerald A. Grant, Nicola Marchi, Emilio Perucca, and Damir Janigro. “Sertraline-induced potentiation of the CYP3A4-dependent neurotoxicity of carbamazepine: an in vitro study.Epilepsia 56, no. 3 (March 2015): 439–49. https://doi.org/10.1111/epi.12923.
Ghosh C, Hossain M, Spriggs A, Ghosh A, Grant GA, Marchi N, et al. Sertraline-induced potentiation of the CYP3A4-dependent neurotoxicity of carbamazepine: an in vitro study. Epilepsia. 2015 Mar;56(3):439–49.
Ghosh, Chaitali, et al. “Sertraline-induced potentiation of the CYP3A4-dependent neurotoxicity of carbamazepine: an in vitro study.Epilepsia, vol. 56, no. 3, Mar. 2015, pp. 439–49. Pubmed, doi:10.1111/epi.12923.
Ghosh C, Hossain M, Spriggs A, Ghosh A, Grant GA, Marchi N, Perucca E, Janigro D. Sertraline-induced potentiation of the CYP3A4-dependent neurotoxicity of carbamazepine: an in vitro study. Epilepsia. 2015 Mar;56(3):439–449.
Journal cover image

Published In

Epilepsia

DOI

EISSN

1528-1167

Publication Date

March 2015

Volume

56

Issue

3

Start / End Page

439 / 449

Location

United States

Related Subject Headings

  • Time Factors
  • Sertraline
  • Selective Serotonin Reuptake Inhibitors
  • Nitrites
  • Neurology & Neurosurgery
  • Microsomes, Liver
  • Ketoconazole
  • Humans
  • Glutathione
  • Gene Expression Regulation