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− 14 C]palmitic acid by hepatic mitochondria, but inhibited by 71% that from [1− 14 C]octanoic acid and by 51% that from [1− 14 C]butyric acid. The activity of the tricarboxylic acid cycle, assessed as the in vitro formation of [ 14 C]CO 2 from [1− 14 C]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 [ 14 C]CO 2 from [1− 14 C]octanoic acid and [1− 14 C]butyric acid, but did not significantly decrease that from [1− 14 C]palmitic acid. After administration of high doses of tianeptine, however, formation of [ 14 C]CO 2 from [1− 14 C]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.