Posted by Franz on November 28, 2004, at 12:41:26
Anyone can explain tianeptine beta oxidation and toxicity?
thanksANTIDEPRESSANTS
Tricyclics. Most tricyclic antidepressants are potentially hepatotoxic. Amineptine, which is not used in the United States, is the most extensively studied. Amineptine-induced liver disease is mainly cholestatic, although moderate necrosis may be seen. An immunoallergic mechanism is suggested by the occurrence of fever, rash, eosinophilia, and positive rechallenge. Amineptine is converted by microsomes into an epoxide that is detoxified by GSH.23,24 Although poor hydroxylators are at decreased risk, 90% of whites are rapid hydroxylators (CYP2D6).23 Thus, hydroxylator status is not a useful predictor of toxicity, although it points to the role of reactive metabolites capable of eliciting an immune response. In vitro cytotoxicity testing indicates that lymphocytes from patients and their first-degree relatives exhibit an increased susceptibility to killing by amineptine metabolites, suggesting an important genetic factor. The basis for the latter is unknown; it does not involve altered GSH or epoxide hydrase,23 although impaired detoxification presumably could be responsible for exposure and sensitization to amineptine metabolites. The metabolism of tianeptine is similar to that of amineptine. The two compounds have an identical heptanoic acid side chain and, rarely, have been associated with microvesicular steatosis.25 The side chain is metabolized by -oxidation, leading to inhibition of medium-and short-chain fatty acid -oxidation.26,45 Thus, both drugs are converted by P450 to reactive metabolites that can induce a hypersensitivity reaction in genetically susceptible individuals. Less commonly, they induce a microvesicular steatosis; in mice, this requires much higher doses than those used therapeutically,27 although one wonders if impaired oxidation of these drugs (in the presence of a competing P450 substrate or in a poor metabolizer) might lead, at least rarely, to the accumulation of sufficient levels of the parent drug to impair -oxidation.
poster:Franz
thread:421307
URL: http://www.dr-bob.org/babble/20041128/msgs/421307.html