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Inhibitory potencies of trimipramine and its main metabolites at human monoamine and organic cation transporters

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Abstract

Rationale

The antidepressant trimipramine shows an atypical pharmacological profile and its mechanism of action is still obscure.

Objectives

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 [3H]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 IC50 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.

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Abbreviations

h:

Human

NAT:

Noradrenaline transporter

SERT:

Serotonin transporter

DAT:

Dopamine transporter

OCT:

Organic cation transporter

MAT:

Monoamine transporter

MPP+ :

Methyl phenyl pyridinium cation

References

  • Amphoux A, Vialou V, Drescher E, Brüss M, Mannoury La Cour C, Rochat C, Millan MJ, Giros B, Bönisch H, Gautron S (2006) Differential pharmacological in vitro properties of organic cation transporters and regional distribution in rat brain. Neuropharmacology 50:941–952

    Article  PubMed  CAS  Google Scholar 

  • Baganz NL, Horton RE, Calderon AS, Owens WA, Munn JL, Watts LT, Koldzic-Zivanovic N, Jeske NA, Koek W, Toney GM, Daws LC (2008) Organic cation transporter 3: keeping the brake on extracellular serotonin in serotonin-transporter-deficient mice. Proc Natl Acad Sci U S A 105:18976–18981

    Article  PubMed  CAS  Google Scholar 

  • Baumann P, Hiemke C, Ulrich S, Eckermann G, Gaertner I, Gerlach M, Kuss HJ, Laux G, Müller-Oerlinghausen B, Rao ML, Riederer P, Zernig G, Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (2004) The AGNP-TDM expert group consensus guidelines: therapeutic drug monitoring in psychiatry. Pharmacopsychiatry 37:243–265

    Article  PubMed  CAS  Google Scholar 

  • Busch AE, Quester S, Ulzheimer JC, Gorboulev V, Akhoundova A, Waldegger S, Lang F, Koepsell H (1996) Monoamine neurotransmitter transport mediated by the polyspecific cation transporter rOCT1. FEBS Lett 395:153–156

    Article  PubMed  CAS  Google Scholar 

  • Cheng Y, Prusoff WH (1973) Relationship between the inhibition constant (K1) and the concentration of inhibitor which causes 50 percent inhibition (I50) of an enzymatic reaction. Biochem Pharmacol 22:3099–3108

    Article  PubMed  CAS  Google Scholar 

  • Eap CB, Bender S, Gastpar M, Fischer W, Haarmann C, Powell K, Jonzier-Perey M, Cochard N, Baumann P (2000) Steady state plasma levels of the enantiomers of trimipramine and of its metabolites in CYP2D6-, CYP2C19- and CYP3A4/5-phenotyped patients. Ther Drug Monit 22:209–214

    Article  PubMed  CAS  Google Scholar 

  • Eikmeier G, Muszynski K, Berger M, Gastpar M (1990) High-dose trimipramine in acute schizophrenia. Preliminary results of an open trial. Pharmacopsychiatry 23:212–214

    Article  PubMed  CAS  Google Scholar 

  • Eikmeier G, Berger M, Lodemann E, Muszynski K, Kaumeier S, Gastpar M (1991) Trimipramine—an atypical neuroleptic? Int Clin Psychopharmacol 6:147–153

    Article  PubMed  CAS  Google Scholar 

  • Feng N, Mo B, Johnson PL, Orchinik M, Lowry CA, Renner KJ (2005) Local inhibition of organic cation transporters increases extracellular serotonin in the medial hypothalamus. Brain Res 1063:69–76

    Article  PubMed  CAS  Google Scholar 

  • Glotzbach KR, Preskorn S (1982) Brain concentrations of tricyclic antidepressants: single-dose kinetics and relationship to plasma concentrations in chronically dosed rats. Psychopharmacology 78:25–27

    Article  PubMed  CAS  Google Scholar 

  • Gross G, Xin X, Gastpar M (1991) Trimipramine: pharmacological reevaluation and comparison with clozapine. Neuropharmacology 30:1159–1166

    Article  PubMed  CAS  Google Scholar 

  • Gründemann D, Schechinger B, Rappold GA, Schömig E (1998) Molecular identification of the corticosterone-sensitive extraneuronal catecholamine transporter. Nat Neurosci 1:349–351

    Article  PubMed  Google Scholar 

  • Haenisch B, Bönisch H (2010) Interaction of the human plasma membrane monoamine transporter (hPMAT) with antidepressants and antipsychotics. Naunyn Schmiedebergs Arch Pharmacol 381:33–39

    Article  PubMed  CAS  Google Scholar 

  • Hauser K, Olpe HR, Jones RS (1985) Trimipramine, a tricyclic antidepressant exerting atypical actions on the central noradrenergic system. Eur J Pharmacol 111:23–30

    Article  PubMed  CAS  Google Scholar 

  • Hiemke C, Baumann P, Laux G, Kuss HJ (2005) Therapeutisches Drug-Monitoring in der Psychiatrie. Konsensus-Leitlinie der AGNP. Psychopharmakotherapie 12:166–182

    Google Scholar 

  • Kirchheiner J, Müller G, Meineke I, Wernecke KD, Roots I, Brockmöller J (2003a) Effects of polymorphisms in CYP2D6, CYP2C9, and CYP2C19 on trimipramine pharmacokinetics. J Clin Psychopharmacol 23:459–466

    Article  CAS  Google Scholar 

  • Kirchheiner J, Sasse J, Meineke I, Roots I, Brockmöller J (2003b) Trimipramine pharmacokinetics after intravenous and oral administration in carriers of CYP2D6 genotypes predicting poor, extensive and ultrahigh activity. Pharmacogenetics 13:721–728

    Article  CAS  Google Scholar 

  • Koepsell H, Lips K, Volk C (2007) Polyspecific organic cation transporters: structure, function, physiological roles, and biopharmaceutical implications. Pharm Res 24:1227–1251

    Article  PubMed  CAS  Google Scholar 

  • Kopanski C, Türck M, Schultz JE (1983) Effects of long-term treatment of rats with antidepressants on adrenergic-receptor sensitivity in cerebral cortex: Structure activity study. Neurochem Int 5:649–659

    Article  PubMed  CAS  Google Scholar 

  • Künzel HE, Ackl N, Hatzinger M, Held K, Holsboer-Trachsler E, Ising M, Kaschka W, Kasper S, Konstantinidis A, Sonntag A, Uhr M, Yassouridis A, Holsboer F, Steiger A (2009) Outcome in delusional depression comparing trimipramine monotherapy with a combination of amitriptyline and haloperidol—a double-blind multicenter trial. J Psychiatr Res 43:702–710

    Article  PubMed  Google Scholar 

  • Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275

    PubMed  CAS  Google Scholar 

  • Maurer H (1989) Metabolism of trimipramine in man. Arzneimittelforschung 39:101–103

    PubMed  CAS  Google Scholar 

  • Randrup A, Braestrup C (1977) Uptake inhibition of biogenic amines by newer antidepressant drugs: relevance to the dopamine hypothesis of depression. Psychopharmacology (Berl) 53:309–314

    Article  CAS  Google Scholar 

  • Richelson E, Nelson A (1984) Antagonism by antidepressants of neurotransmitter receptors of normal human brain in vitro. J Pharmacol Exp Ther 230:94–102

    PubMed  CAS  Google Scholar 

  • Schmitt A, Mössner R, Gossmann A, Fischer IG, Gorboulev V, Murphy DL, Koepsell H, Lesch KP (2003) Organic cation transporter capable of transporting serotonin is up-regulated in serotonin transporter-deficient mice. J Neurosci Res 71:701–709

    Article  PubMed  CAS  Google Scholar 

  • Seeman P (1992) Dopamine receptor sequences. Therapeutic levels of neuroleptics occupy D2 receptors, clozapine occupies D4. Neuropsychopharmacology 7:261–284

    PubMed  CAS  Google Scholar 

  • Steiger A, Von Bardeleben U, Guldner J, Lauer C, Rothe B, Holsboer F (1993) The sleep EEG and nocturnal hormonal secretion studies on changes during the course of depression and on effects of CNS-active drugs. Prog Neuropsychopharmacol Biol Psychiatry 17:125–137

    Article  PubMed  CAS  Google Scholar 

  • Tatsumi M, Groshan K, Blakely RD, Richelson E (1997) Pharmacological profile of antidepressants and related compounds at human monoamine transporters. Eur J Pharmacol 340:249–258

    Article  PubMed  CAS  Google Scholar 

  • Weigmann H, Härtter S, Bagli M, Hiemke C (2000) Steady state concentrations of clomipramine and its major metabolite desmethylclomipramine in rat brain after oral administration of clomipramine. Eur Neuropsychopharmacol 10:401–405

    Article  PubMed  CAS  Google Scholar 

  • Wenge B, Bönisch H (2009) Interference of the noradrenergic neurotoxin DSP4 with neuronal and nonneuronal monoamine transporters. Naunyn Schmiedebergs Arch Pharmacol 380:523–529

    Article  PubMed  CAS  Google Scholar 

  • Wu X, Kekuda R, Huang W, Fei YJ, Leibach FH, Chen J, Conway SJ, Ganapathy V (1998) Identity of the organic cation transporter OCT3 as the extraneuronal monoamine transporter (uptake2) and evidence for the expression of the transporter in the brain. J Biol Chem 273:32776–32786

    Article  PubMed  CAS  Google Scholar 

  • Wultsch T, Grimberg G, Schmitt A, Painsipp E, Wetzstein H, Breitenkamp AF, Gründemann D, Schömig E, Lesch KP, Gerlach M, Reif A (2009) Decreased anxiety in mice lacking the organic cation transporter 3. J Neural Transm 116:689–697

    Article  PubMed  CAS  Google Scholar 

  • Yu PH, Boulton AA (1990) Effect of trimipramine, an atypical tricyclic antidepressant, on the activities of various enzymes involved in the metabolism of biogenic amines. Prog Neuropsychopharmacol Biol Psychiatry 14:409–416

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank Natalie Lobes for the skilful technical assistance and Dr. Wilhelm Fischer for his help. This work was supported by grants of BONFOR; B. Haenisch received a scholarship from the Studienstiftung des Deutschen Volkes.

Conflicts of interest

There are no conflicts of interests.

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Author notes

  1. Britta Haenisch

    Present address: Institute of Human Genetics, Department of Genomics, Life and Brain Center, University of Bonn, Sigmund-Freud-Strasse 25, 53127, Bonn, Germany

Authors and Affiliations

  1. Institute of Pharmacology and Toxicology, Biomedical Center, University of Bonn, Sigmund-Freud-Strasse 25, 53127, Bonn, Germany

    Britta Haenisch & Heinz Bönisch

  2. Department of Psychiatry and Psychotherapy, University Medical Center, Johannes Gutenberg University Mainz, Untere Zahlbacher Strasse 8, 55131, Mainz, Germany

    Christoph Hiemke

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  1. Britta Haenisch
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Correspondence to Heinz Bönisch.

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Haenisch, B., Hiemke, C. & Bönisch, H. Inhibitory potencies of trimipramine and its main metabolites at human monoamine and organic cation transporters. Psychopharmacology 217, 289–295 (2011). https://doi.org/10.1007/s00213-011-2281-9

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  • DOI: https://doi.org/10.1007/s00213-011-2281-9

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