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Sertraline‐induced potentiation of the CYP3A4‐dependent neurotoxicity of carbamazepine: An in vitro study
Author(s) -
Ghosh Chaitali,
Hossain Mohammad,
Spriggs Addison,
Ghosh Arnab,
Grant Gerald A.,
Marchi Nicola,
Perucca Emilio,
Janigro Damir
Publication year - 2015
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1111/epi.12923
Subject(s) - pharmacology , neurotoxicity , chemistry , cytotoxicity , glutathione , toxicity , cyp3a4 , biochemistry , cytochrome p450 , in vitro , medicine , metabolism , enzyme , organic chemistry
Summary 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 CYP s 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 ( HBMEC s), 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 CYP 3A4 in causing neurotoxicity, drug metabolism was compared to cell death in HEK CYP 3A4 overexpressed and cells pretreated with the CYP 3A4 inhibitor ketoconazole. Results In all cellular systems tested, exposure to CBZ (127 μ m ) or SRT (5 μ m ) alone caused negligible cytotoxicity. By contrast CBZ , tested at a much lower concentration (17 μ m ) in combination with SRT (5 μ m ), produced prominent cytotoxicity within 15 min exposure. In neurons and HBMEC s, cytotoxicity was associated with increased nitrite levels, suggesting involvement of free radicals as a pathogenetic mechanism. Pretreatment of HBMEC s 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 CYP 3A4, and prevented by CYP 3A4 inhibitor. Significance These results demonstrate an unexpected neurotoxic interaction between CBZ and SRT , apparently related to increased CYP 3A4‐mediated production of reactive CBZ metabolites. The potential clinical implications of these findings are discussed.