Journal of Neural Transmission

, Volume 113, Issue 3, pp 387–397

Region specific distribution of levomepromazine in the human brain

  • J. Kornhuber
  • H. Weigmann
  • J. Röhrich
  • J. Wiltfang
  • S. Bleich
  • I. Meineke
  • R. Zöchling
  • S. Härtter
  • P. Riederer
  • C. Hiemke


Objective: The aim of this study was to examine concentrations of levomepromazine and its metabolite desmethyl-levomepromazine in different regions of human brain and in relationship to drug-free time.

Methods: Drug concentrations were measured in up to 43 regions of 5 postmortem human brains of patients previously treated with levomepromazine. To enable statistical comparison across brain regions several smaller brain areas were put together to form larger brain areas (cortex cerebri, limbic system, cerebellum, basal ganglia, thalamus). Mean values of drug concentrations in these larger brain areas were used in a repeated measurement ANOVA to analyze for region specific distribution. The elimination half-life in brain tissue was estimated with a NONMEM population kinetic analysis using the mean value of all brain regions of an individual case.

Results: Levomepromazine and desmethyl-levomepromazine appear to accumulate in human brain tissue relative to blood. Mean concentrations differed largely between individual brains, in part due to differences in dose of drug, duration of treatment and drug-free time before death. There was an apparent region-specific difference in levomepromazine concentrations with highest values in the basal ganglia (mean 316 ng/g) and lowest values in the cortex cerebri (mean 209 ng/g). The elimination half-life from brain tissue is longer than from blood and was calculated to be about one week. Similar results were obtained with desmethyl-levomepromazine.

Conclusions: Levomepromazine shows a region-specific distribution in the human brain with highest values in the basal ganglia. This might be the consequence of low expression of the metabolic enzyme Cyp2D6 in the basal ganglia. If this finding is true also for other neuroleptic drugs it might increase our understanding of preferential toxicity of neuroleptic drugs against basal ganglia structures and higher volumes of basal ganglia of neuroleptic-treated patients. Furthermore, patients exposed to levomepromazine cannot be considered to be free of residual effects of the drug for a number of weeks after withdrawal.

Keywords: Human, postmortem brain, pharmacokinetics, levomepromazine, neuroleptic drug, region-specific distribution. 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Afifi, A-HM, Way, EL 1967Estimation of methotrimeprazine in brain and correlation of brain levels with pharmacologic activity.J Pharm Sci56720724PubMedGoogle Scholar
  2. Afifi, A-HM, Way, EL 1968Studies on the biologic disposition of methotrimeprazine.J Pharmacol Exp Ther160397406PubMedGoogle Scholar
  3. Allgén LG, Hellström L, Sant’Orp CJ (1963) On the metabolism and elimination of the psychotropic phenothiazine drug levomepromazine (NozinanR) in man. Acta Psychiatr Neurol Scand [Suppl 39] [Suppl 169]: 366–381Google Scholar
  4. Andersson, C, Hamer, RM, Lawler, CP, Mailman, RB, Lieberman, JA 2002Striatal volume changes in the rat following long-term administration of typical and atypical antipsychotic drugs.Neuropsychopharmacology27143151CrossRefPubMedGoogle Scholar
  5. Bal, A, Smialowska, M 1987The influence of some antidepressant drugs on the nuclear volume of rat cingulate cortex cells in culture.Neuroscience22671674CrossRefPubMedGoogle Scholar
  6. Bal-Klara, A, Bird, MM 1990The effects of various antidepressant drugs on the fine-structure of neurons of the cingulate cortex in culture.Neuroscience37685692CrossRefPubMedGoogle Scholar
  7. Beal SL, Sheiner LB (1992) NONMEM Users Guides, NONMEM Project Group, San Francisco. University of California, San FranciscoGoogle Scholar
  8. Britto, MR, Wedlund, PJ 1992Cytochrome P-450 in the brain. Potential evolutionary and therapeutic relevance of localization of drug-metabolizing enzymes.Drug Metab Dispos20446450PubMedGoogle Scholar
  9. Chakos, MH, Liebermann, JA, Alvir, J, Bilder, RM, Ashtari, M 1995Caudate nuclei volumes in schizophrenic patients treated with typical antipsychotics or clozapine.Lancet345456457CrossRefPubMedGoogle Scholar
  10. Chakos, MH, Shirakawa, O, Lieberman, J, Lee, H, Bilder, R, Tamminga, CA 1998Striatal enlargement in rats chronically treated with neuroleptic.Biol Psychiatry44675684CrossRefPubMedGoogle Scholar
  11. Cohen, BM, Babb, S, Campbell, A, Baldessarini, RJ 1988Persistence of haloperidol in the brain.Arch Gen Psychiatry45879880PubMedGoogle Scholar
  12. Corson, PW, Nopoulos, P, Miller, DD, Arndt, S, Andreasen, NC 1999Change in basal ganglia volume over 2 years in patients with schizophrenia: typical versus atypical neuroleptics.Am J Psychiatry15612001204PubMedGoogle Scholar
  13. Dahl, SG 1976Pharmacokinetics of methotrimeprazine after single and multiple doses.Clin Pharmacol Ther19435442PubMedGoogle Scholar
  14. Dahl, SG 1982Active metabolites of neuroleptic drugs: possible contribution to therapeutic and toxic effects.Ther Drug Monit43340PubMedGoogle Scholar
  15. Dahl, SG, Garle, M 1977Identification of nonpolar methotrimeprazine metabolites in plasma and urine by GLC-mass spectrometry.J Pharm Sci66190193PubMedGoogle Scholar
  16. Dahl, SG, Johnsen, H, Lee, CR 1982Gas chromatographic mass spectrometric identification of O-demethylated and mono-hydroxylated metabolites of levomepromazine in blood from psychiatric patients by selected ion recording with high resolution.Biomed Mass Spectrometry9534538Google Scholar
  17. Dahl, SG, Strandjord, RE, Sigfusson, S 1977Pharmacokinetics and relative bioavailability of levomepromazine after repeated administration of tablets and syrup.Eur J Clin Pharmacol11305310CrossRefPubMedGoogle Scholar
  18. Daniel, WA 2003Mechanisms of cellular distribution of psychotropic drugs. Significance for drug action and interactions.Prog Neuropsychopharmacol Biol Psychiatry276573CrossRefPubMedGoogle Scholar
  19. Daniel, WA, Wójcikowski, J 1997Contribution of lysosomal trapping to the total tissue uptake of psychotropic drugs.Pharmacol Toxicol806268PubMedGoogle Scholar
  20. Daniel, WA, Wojcikowski, J, Palucha, A 2001Intracellular distribution of psychotropic drugs in the grey and white matter of the brain: the role of lysosomal trapping.Br J Pharmacol134807814CrossRefPubMedGoogle Scholar
  21. Doraiswamy, PM, Tupler, LA, Krishnan, KR 1995Neuroleptic treatment and caudate plasticity [published erratum appears in Lancet (1995) 345(8959): 1250].Lancet345734735PubMedGoogle Scholar
  22. El Ela, AA, Härtter, S, Schmitt, U, Hiemke, C, Spahn-Langguth, H, Langguth, P 2004Identification of P-glycoprotein substrates and inhibitors among psychoactive compounds – implications for pharmacokinetics of selected substrates.J Pharm Pharmacol56967975CrossRefPubMedGoogle Scholar
  23. Gsell, W, Lange, KW, Pfeuffer, R, Heckers, S, Heinsen, H, Senitz, D, Jellinger, K, Ransmayr, G, Wichart, I, Vock, R, Beckmann, H, Riederer, P 1993How to run a brain bank. A report from the Austro-German brain bank.J Neural Transm [Suppl]393170Google Scholar
  24. Gunne, LM, Haggstrom, JE, Sjoquist, B 1984Association with persistent neuroleptic-induced dyskinesia of regional changes in brain GABA synthesis.Nature309347349CrossRefPubMedGoogle Scholar
  25. Gur, RE, Maany, V, Mozley, PD, Swanson, C, Bilker, W, Gur, RC 1998Subcortical MRI volumes in neuroleptic-naive and treated patients with schizophrenia.Am J Psychiatry15517111717PubMedGoogle Scholar
  26. Hals, PA, Dahl, SG 1994Effect of levomepromazine and metabolites on debrisoquine hydroxylation in the rat.Pharmacol Toxicol75255260PubMedGoogle Scholar
  27. Hara, E, Reinach, PS, Wen, Q, Iserovich, P, Fischbarg, J 1999Fluoxetine inhibits K+ transport pathways (K+ efflux, Na+–K+–2Cl cotransport, and Na+ pump) underlying volume regulation in corneal endothelial cells.J Membr Biol1717585CrossRefPubMedGoogle Scholar
  28. Heckers, S, Heinsen, H, Heinsen, Y, Beckmann, H 1991Cortex, white matter, and basal ganglia in schizophrenia: a volumetric postmortem study.Biol Psychiatry29556566CrossRefPubMedGoogle Scholar
  29. Hilberg, T, Mørland, J, Bjørneboe, A 1994Postmortem release of amitriptyline from the lungs; a mechanism of postmortem drug redistribution.Forensic Sci Int644755CrossRefPubMedGoogle Scholar
  30. Hoffmann, EK, Simonsen, LO 1989Membrane mechanisms in volume and pH regulation in vertebrate cells.Physiol Rev69315382PubMedGoogle Scholar
  31. Janssen, PAJ, Soudijn, W, Wijngaarden, I, Dresse, A 1968Pimozide, a chemically novel, highly potent and orally long-acting neuroleptic drug. III. Regional distribution of pimozide and of haloperidol in the dog brain.Arzneimittelforschung18282287PubMedGoogle Scholar
  32. Johnsen, H, Dahl, SG 1982Identification of O-demethylated and ring-hydroxylated metabolites of methotrimeprazine (levomepromazine) in man.Drug Metab Dispos106367PubMedGoogle Scholar
  33. Kornhuber, J, Retz, W, Riederer, P 1995Slow accumulation of psychotropic substances in the human brain. Relationship to therapeutic latency of neuroleptic and antidepressant drugs?J Neural Transm [Suppl]46311319Google Scholar
  34. Kornhuber, J, Schultz, A, Wiltfang, J, Meineke, I, Gleiter, CH, Zöchling, R, Boissl, K-W, Leblhuber, F, Riederer, P 1999Persistence of haloperidol in human brain tissue.Am J Psychiatry156885890PubMedGoogle Scholar
  35. Korpi, ER, Kleinman, JE, Costakos, DT, Linnoila, M, Wyatt, RJ 1984Reduced haloperidol in the post-mortem brains of haloperidol-treated patients.Psychiatry Res11259269CrossRefPubMedGoogle Scholar
  36. Laduron, PM, Janssen, PF, Leysen, JE 1978Spiperone: a ligand of choice for neuroleptic receptors. 2. Regional distribution and in vivo displacement of neuroleptic drugs.Biochem Pharmacol27317321PubMedGoogle Scholar
  37. Martindale. The Extra Pharmacapoeia (1993). In: Reynolds JEF (ed) The Pharmaceutical Press, London, pp xxi–xxvGoogle Scholar
  38. Meyer, UA, Amrein, R, Balant, LP, Bertilsson, L, Eichelbaum, M, Guentert, TW, Henauer, S, Jackson, P, Laux, G, Mikkelsen, H, Peck, C, Pollock, BG, Priest, R, Sjöqvist, F, Delini-Stula, A 1996Antidepressants and drug-metabolizing enzymes – expert group report.Acta Psychiatr Scand937179PubMedGoogle Scholar
  39. Miller, DD, Andreasen, NC, O’Leary, DS, Rezai, K, Watkins, GL, Ponto, LL, Hichwa, RD 1997aEffect of antipsychotics on regional cerebral blood flow measured with positron emission tomography [published erratum appears in Neuropsychopharmacology (1998) 18(4): 323–324].Neuropsychopharmacology17230240CrossRefGoogle Scholar
  40. Miller, DD, Rezai, K, Alliger, R, Andreasen, NC 1997bThe effect of antipsychotic medication on relative cerebral blood perfusion in schizophrenia: assessment with technetium-99 m hexamethyl-propyleneamine oxime single photon emission computed tomography.Biol Psychiatry41550559CrossRefGoogle Scholar
  41. Morel, E, Lloyd, KG, Dahl, SG 1987Anti-apomorphine effects of phenothiazine drug metabolites.Psychopharmacology Berl926872CrossRefPubMedGoogle Scholar
  42. Norris, PJ, Hardwick, JP, Emson, PC 1996Regional distribution of cytochrome P450 2D1 in the rat central nervous system.J Comp Neurol366244258CrossRefPubMedGoogle Scholar
  43. Ravindranath, V, Bhamre, S, Bhagwat, SV, Anandatheerthavarada, HK, Shankar, SK, Tirumalai, PS 1995Xenobiotic metabolism in brain.Toxicol Lett82–83633638PubMedGoogle Scholar
  44. Schilter, B, Omiecinski, CJ 1993Regional distribution and expression modulation of cytochrome P-450 and epoxide hydrolase mRNAs in the rat brain.Mol Pharmacol44990996PubMedGoogle Scholar
  45. Sellinger, OZ, Hiatt, RA 1968Cerebral lysosomes. IV. The regional and intracellular distribution of arylsulfatase and evidence for two populations of lysosomes in rat brain.Brain Res7191200CrossRefPubMedGoogle Scholar
  46. Sklair-Tavron, L, Shi, WX, Lane, SB, Harris, HW, Bunney, BS, Nestler, EJ 1996Chronic morphine induces visible changes in the morphology of mesolimbic dopamine neurons.Proc Natl Acad Sci USA931120211207CrossRefPubMedGoogle Scholar
  47. Sunderland, T, Cohen, BM 1987Blood to brain distribution of neuroleptics.Psychiatry Res20299305CrossRefPubMedGoogle Scholar
  48. Tokunaga, H, Kudo, K, Imamura, T, Jitsufuchi, N, Ohtsuka, Y, Ikeda, N 1997Plasma concentrations of antipsychotic drugs in psychiatric inpatients.Nippon Hoigaku Zasshi51417422PubMedGoogle Scholar
  49. Weigmann, H, Härtter, S, Hiemke, C 1998Automated determination of clomipramine and its major metabolites in human and rat serum by high-performance liquid chromatography with on-line column-switching.J Chromatogr B Biomed Sci Appl710227233CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag/Wien 2005

Authors and Affiliations

  • J. Kornhuber
    • 1
  • H. Weigmann
    • 2
  • J. Röhrich
    • 3
  • J. Wiltfang
    • 1
  • S. Bleich
    • 1
  • I. Meineke
    • 4
  • R. Zöchling
    • 5
  • S. Härtter
    • 2
  • P. Riederer
    • 6
  • C. Hiemke
    • 2
  1. 1.Department of PsychiatryUniversity of ErlangenGermany
  2. 2.Department of PsychiatryUniversity of MainzGermany
  3. 3.Department of Forensic MedicineUniversity of MainzGermany
  4. 4.Department of Clinical PharmacologyUniversity of GöttingenGermany
  5. 5.Lower Austria LKH for PsychiatryMauer/AmstettenAustria
  6. 6.Department of PsychiatryUniversity of WürzburgGermany

Personalised recommendations