title: In vitro biotransformation of amitriptyline and imipramine with rat hepatic S9 fraction: evaluation of the toxicity with Spirotox and Thamnotoxkit F Tests.
abstract: Pharmaceutical products, as well as their related metabolites, end up in the aquatic environment after use. Little is known about the effects and the hazard of exposure to drugs for aquatic organisms. This study was designed to assess the ecotoxicity of amitriptyline (AMI), imipramine (IMI), and their metabolites. The tested drugs were very toxic to the protozoan Spirostomum ambiguum and the crustacean Thamnocephalus platyurus with the LC50 values around 1 mg l(-1). Moreover, simple additivity occurs between the drugs and their N-desmethyl metabolites. Tested compounds were incubated with S9 rat hepatocyte fraction at 37 degrees C for 4 hours. Unchanged drugs and metabolites were determined using high-pressure liquid chromatography-photodiode array detector. AMI and IMI were biotransformed almost completely. Three AMI and IMI metabolites were detected: desmethyl-, didesmethyl-, and N-oxide. The toxicity of the deproteinated reaction mixtures (TU) was compared to the toxicity equivalency units (TEU) calculated based on the concentrations of the drugs and their LC50 values. It has been demonstrated that the toxicity of mixture of metabolites to Spirotox and Thamnotoxkit F is higher than the predicted value calculated from the concentrations of the drugs and their N-desmethylated derivatives in the sample. The results indicate that the harmfulness of the drug metabolites should be taken into consideration in the ecotoxicological studies.
authors.affiliation: Department of Environmental Health Sciences, Medical University of Warsaw, Warsaw, Poland. grzenaja@wp.pl
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Nałecz-Jawecki
mesh_terms: D000639:Amitriptyline / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D033202:Anostraca / Q000187:drug effects*; D001711:Biotransformation; D016798:Ciliophora / Q000187:drug effects*; D003891:Desipramine / Q000633:toxicity; D007099:Imipramine / Q000378:metabolism / Q000633:toxicity*; D007928:Lethal Dose 50; D008099:Liver / Q000378:metabolism; D008297:Male; D009661:Nortriptyline / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D018675:Toxicity Tests; D014874:Water Pollutants, Chemical / Q000378:metabolism / Q000633:toxicity*
chemical_list: D014874:Water Pollutants, Chemical; D000639:Amitriptyline; D009661:Nortriptyline; D007099:Imipramine; D003891:Desipramine