Metabolic activation of the new tricyclic antidepressant
tianeptine by human liver cytochrome P450

by
Larrey D, Tinel M, Letteron P, Maurel P, Loeper J, Belghiti J, Pessayre D.
Unite de Recherches de Physiopathologie Hepatique (INSERM U 24),
Hopital Beaujon, Clichy, France.
Biochem Pharmacol. 1990 Aug 1;40(3):545-50.


ABSTRACT

Incubation of [14C]tianeptine (0.5 mM) with human liver microsomes and a NADPH-generating system resulted in the in vitro covalent binding of a tianeptine metabolite to microsomal proteins. This covalent binding required oxygen and NADPH. It was decreased by piperonyl butoxide (4 mM) by 81%, and SKF 525-A (4 mM) by 87%, two relatively non-specific inhibitors of cytochrome P450, and by glutathione (4 mM) by 70%, a nucleophile. Covalent binding was decreased by 54% in the presence of troleandomycin (0.1 mM), a specific inhibitor of the glucocorticoid-inducible cytochrome P450 IIIA3, but remained unchanged in the presence of quinidine (0.1 mM) or dextromethorphan (0.1 mM), two inhibitors of cytochrome P450 IID6. Preincubation with IgG antibodies directed against cytochrome P450 IIIA3 decreased covalent binding by 65% whereas either preimmune IgG or IgG antibodies directed against P450 IA1, an isoenzyme inducible by polycyclic aromatic compounds, exhibited no significant inhibitory effect. We conclude that tianeptine is activated by human liver cytochrome P450 into a reactive metabolite. This activation is mediated in part by glucocorticoid-inducible isoenzymes but not by P450 IID6 (the isoenzyme which oxidizes debrisoquine) nor by P450 IA1 (an isoenzyme inducible by polycyclic aromatic compounds). The predictive value of this study regarding possible idiosyncratic and immunoallergic reactions in humans remains unknown.


Cytochrome P450
Pharmacodynamics
Serotonin/forebrain
Tianeptine (Stablon)
Tianeptine: structure
Tianeptine analogues
Microvesicular steatosis
Mitochondrial beta-oxidation
Food and tianeptine metabolism
Tianeptine for anxious depressives
Chronic renal failure and haemodialysis
Electrophysiological effects of tianeptine
Tianeptine-induced serotonin uptake increase
Tianeptine: ultra-high dose metabolism study
Place of tianeptine (Stablon) among antidepressants
Antidepressant and selective serotonin reuptake enhancer


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