Tianeptine, a new tricyclic antidepressant metabolized by β-oxidation of its heptanoic side chain, inhibits the mitochondrial oxidation of medium and short chain fatty acids in mice

Abstract

Tianeptine is a new tricyclic antidepressant which is metabolized mainly by β-oxidation of its heptanoic side chain. We determined the effects of tianeptine on the mitochondrial oxidation of natural fatty acids in mice. In vitro, tianeptine (0.5 mM) inhibited by only 32% the formation of β-oxidation products from [1− 14C]palmitic acid by hepatic mitochondria, but inhibited by 71% that from [1− 14C]octanoic acid and by 51% that from [1− 14C]butyric acid. The activity of the tricarboxylic acid cycle, assessed as the in vitro formation of [ 14C]CO 2 from [1− 14C]acetylcoenzyme A was decreased by 51% in the presence of tianeptine (0.5 mM). The inhibition of both β-oxidation and the tricarboxylic acid cycle appeared reversible in mitochondria from mice exposed to tianeptine in vivo but incubated in vitro without tianeptine. In vivo, administration of tianeptine (0.0625 mmol/kg i.p.), decreased by 53 and 58%, respectively, the formation of [ 14C]CO 2 from [1− 14C]octanoic acid and [1− 14C]butyric acid, but did not significantly decrease that from [1− 14C]palmitic acid. After administration of high doses of tianeptine, however, formation of [ 14C]CO 2 from [1− 14C]palmitic acid became inhibited as well, transiently after 0.25 mmol/kg and durably (>24 hr) after 0.75 mmol/kg i.p. Hepatic triglycerides were increased 24 hr after administration of 0.75 mmol/kg i.p. of tianeptine, but not after 0.25 mmol/kg i.p. Microvesicular steatosis of the liver was observed in some mice after 0.75 mmol/kg i.p., but not after 0.5 mmol/kg i.p. We conclude that tianeptine inhibits the oxidation of medium- and short-chain fatty acids in mice. Microvesicular steatosis, however, requires very large doses in mice (0.75 mmol/kg i.p., i.e. 600-times the oral dose in humans), and is therefore unlikely to occur in humans.