title: Inhibitory potencies of trimipramine and its main metabolites at human monoamine and organic cation transporters.
abstract: BACKGROUND
  The antidepressant trimipramine shows an atypical pharmacological profile and its mechanism of action is still obscure.
  
  
  OBJECTIVE
  The present study investigated whether trimipramine and three of its metabolites interact with targets of other antidepressants, namely, the human monoamine transporters for noradrenaline (hNAT), serotonin (hSERT), and dopamine (hDAT), and with the human organic cation transporters (hOCT1, hOCT2, and hOCT3) which are expressed in the brain and are known to be involved in the uptake of monoamines.
  
  
  METHODS
  HEK293 cells heterologously expressing the abovementioned transporters were used to determine the inhibition of [(3)H]MPP(+) uptake by trimipramine and its main metabolites.
  
  
  RESULTS
  At concentrations up to 30 μM, all transporters, except hOCT3, were inhibited by all examined substances. With IC(50) values between 2 and 10 μM, trimipramine inhibited hSERT, hNAT, hOCT1, and hOCT2, whereas clearly higher concentrations were needed for half-maximal inhibition of hDAT. Desmethyl-trimipramine showed about the same potencies as trimipramine, whereas 2-hydroxy-trimipramine was less potent at hNAT, hSERT, and hOCT1. Trimipramine-N-oxide preferentially inhibited hSERT.
  
  
  CONCLUSIONS
  Neither trimipramine nor its metabolites are highly potent inhibitors of the examined monoamine transporters. However, since at a steady state the sum of the concentrations of the parent compound and its active metabolites is almost two times higher than the plasma concentration of trimipramine and since it is known that tricyclic antidepressants accumulate in the brain (up to tenfold), at least partial inhibition by trimipramine and its metabolites of hSERT and hNAT (but not of hOCT3) may contribute to the antidepressant action of trimipramine.
authors.affiliation: Institute of Pharmacology and Toxicology, Biomedical Center, University of Bonn, Sigmund-Freud-Strasse 25, 53127, Bonn, Germany.
authors.forename: Britta
authors.initials: B
authors.lastname: Haenisch
authors.forename: Christoph
authors.initials: C
authors.lastname: Hiemke
authors.forename: Heinz
authors.initials: H
authors.lastname: Bönisch
mesh_terms: D000928:Antidepressive Agents / Q000378:metabolism / Q000494:pharmacology; D015306:Biogenic Monoamines / Q000378:metabolism*; D018929:Cell Culture Techniques; D003627:Data Interpretation, Statistical; D057809:HEK293 Cells; D006801:Humans; D015394:Molecular Structure; D050479:Neurotransmitter Transport Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D027701:Organic Cation Transport Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D012044:Regression Analysis; D014162:Transfection; D014299:Trimipramine / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000928:Antidepressive Agents; D015306:Biogenic Monoamines; D050479:Neurotransmitter Transport Proteins; D027701:Organic Cation Transport Proteins; D014299:Trimipramine