Skip to main content
SpringerLink
Log in

Chirality and Drugs Used in Psychiatry: Nice to Know or Need to Know?

  • Published:
Cellular and Molecular Neurobiology Aims and scope Submit manuscript

Abstract

1. Many drugs used to treat psychiatric disorders contain a chiral center or a center of unsaturation and are marketed as a mixture of the resultant enantiomers or geometric isomers, respectively. These enantiomers or geometric isomers may differ markedly with regard to their pharmacodynamic and/or pharmacokinetic properties.

2. Examples of the effects of chiral centers or geometric centers on such properties are given for drugs from the following classes: antidepressants (tricyclics, selective serotonin reuptake inhibitors, monoamine oxidase inhibitors, viloxazine, bupropion, trazodone, mianserin, venlaflaxine); benzodiazepines, zoplicone, and antipsychotics.

3. As described in this review, there are several notable examples of psychiatric drugs currently available where the individual enantiomers or geometric isomers differ considerably with regard to factors such as effects on amine transport systems, interactions with receptors and metabolizing enzymes, and clearance rates from the body. Indeed, relatively recent developments in analytical and preparative resolution of racemic and geometric drug mixtures and increased interest in developing new drugs which interact with specific targets, which have been described in detail at the molecular level, have resulted in increased emphasis on stereochemistry in drug development.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

REFERENCES

  • Alebic-Kolbah, T., Kajfez, F., Rendic, S., Sunjic, V., Konowal, A., and Snatzke, G. (1979). Circular dichroism and gel filtration study of binding of prochiral and chiral 1,4-benzodiazepine 2-ones to human serum albumin. Biochem. Pharmacol. 28:2457–2464.

    Google Scholar 

  • Alexander, B. S., and Wood, M. D. (1987). Stereoselective blockade of central [3H] 5-hydroxytryptamine binding to multiple sites (5-HT1A, 5HT1B and 5-HT1C) by mianserin and propranolol. J. Pharm. Pharmacol. 39:664–666.

    Google Scholar 

  • Ariens, E. J. (1984). Stereochemistry, a basis for sophisticated nonsense in pharmacokinetics and clinical pharmacology. Eur. J. Clin. Pharmacol. 26: 663–668.

    Google Scholar 

  • Aspeslet, L. J., Baker, G. B., Coutts, R. T., and Torok-Both, G. A. (1994). The effects of desipramine and iprindole on levels of enantiomers of fluoxetine in rat brain and urine. Chirality 6:86–90.

    Google Scholar 

  • Baier-Weber, B., Prox, A., Wachsmuth, H., and Breyer-Pfaff, U. (1988). Glucuronides of hydroxylated metabolites of amitriptyline and nortriptyline isolated from rat bile. Drug Metab. Dispos. 16:490–496.

    Google Scholar 

  • Baumann, P. (1992). Clinical pharmacokinetics of citalopram and other selective serotogenic reuptake inhibitors (SSRI). Int. Clin. Psychopharmacol. 6:13–20

    Google Scholar 

  • Baumann, P., and Rochat, B. (1995). Comparative pharmacokinetics of selective serotonin reuptake inhibitors: A look behind the mirror. Int. Clin. Psychopharmacol. 10:15–21.

    Google Scholar 

  • Beauchamp, G., Lavoie, P. A., and Elie, R. (1992). Effect of trimipramine on depolarization-induced 45calcium uptake in synaptosomes from the cortex of the rat brain. Neuropharmacology 31:229–234.

    Google Scholar 

  • Benfield, P., and Ward, A. (1986). Fluvoxamine: A review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in depressive illness. Drugs 32:313–334.

    Google Scholar 

  • Bertilsson, L., and Alexanderson, B. (1972). Stereospecific hydroxylation of nortriptyline in man in relationship to interindividual differences in its steady-state plasma level. Eur. J. Clin. Pharmacol. 4:201–205.

    Google Scholar 

  • Bertilsson, L., Mellstrom, B., and Sjöqvist, F. (1979). Pronounced inhibition of noradrenaline uptake by10-hydroxy-metabolites of nortriptyline. Life Sci. 25:1285–1292.

    Google Scholar 

  • Blaschke, G., Hempel, G., and Muller, W. E. (1993). Preparation and analytical separation of the zopiclone enantiomers and determination of their affinity to the benzodiazepine receptor binding site. Chirality 5:419–421.

    Google Scholar 

  • Boireau, A., Blanchard, J.-C., Garret, C., and Julou, L. (1980). The use of thioproperazine, a phenothiazine derivative, as a ligand for neuroleptic receptors. II. In vivo studies. Biochem. Pharmacol. 29:2339.

    Google Scholar 

  • Bowman, W. C., and Rand, M. J. (1980). Textbook of Pharmacology, 2nd ed., Blackwell Scientific, Oxford, pp. 15–16.

    Google Scholar 

  • Brosen, K. (1990). Recent developments in hepatic drug oxidation (implications for clinical pharmacokinetics). Clin. Pharmacokinet. 18:220–239

    Google Scholar 

  • Cahn, R. S., Ingold, C. K., and Prelog, V. (1966). The specification of asymmetric configuration in organic chemistry. Experientia 12:81–124.

    Google Scholar 

  • Caldwell, J. (1992). The importance of stereochemistry in drug action and disposition. J. Clin. Pharmacol. 32:925–929.

    Google Scholar 

  • Caldwell, J. (1996). Importance of stereospecific bioanalytical monitoring in drug development. J. Chromatogr. A 719:3–13.

    Google Scholar 

  • Campbell, D. B. (1990). Selectivity in clinical pharmacokinetics and drug development. Eur. J. Drug Metab. Pharmacokinet. 15:109–125.

    Google Scholar 

  • Camilleri, P., de Baisi, V., and Hutt, A. (1994). Resolving the problem. Chem. Brit. 30:43–46.

    Google Scholar 

  • Case, D. E., and Reeves, P. R. (1975). The disposition and metabolism of viloxazine in humans. Xenobiotica 5:113–129.

    Google Scholar 

  • Cheeta, S., Broekkamp, C., and Willner, P. (1994). Stereospecific reversal of stress-induced anhedonia by mianserin and its (+)-enantiomer. Psychopharmacology 116:523–528.

    Google Scholar 

  • Corbella, A., Gariboldi, P., Jommi, A., Forgione, A., Marcucci, F., Martelli, E., Mussani, E., and Mauri, F. (1973). Stereochemistry of the enzymic 3-hydroxylation of 1,3-dihydro-2H-1,4-benzodiazepine-2-ones. J. Chem. Soc. Chem. Commun. 721–722.

  • Coutts, R. T., and Baker, G.B. (1989). Implications of chirality and geometric isomerism in some psychoactive drugs and their metabolites. Chirality 99–120.

  • Dahl, M. L., Tybring, G., Elwin, C. E., Andreasson, K., Gyllenpalm, M., and Bertilsson, L. (1994). Stereoselective disposition of mianserin is related to debrisoquine hydroxylation. Clin. Pharmacol. Ther. 56:176–183.

    Google Scholar 

  • Drayer, D. E. (1988). Problems in therapeutic drug monitoring: the dilemma of enantiomeric drugs in man. Ther. Drug Monit. 10:1–7.

    Google Scholar 

  • Drayer, D. E. (1986). Pharmacodynamic and pharmacokinetic differences between drug enantiomers in humans: An overview. Clin. Pharmacol. Ther. 40:125–133.

    Google Scholar 

  • Ducharme, J., Fernandez, C., Gimenez, F., and Farinotti, R. (1996). Critical issues in chiral drug analysis in biological fluids by high-performance liquid chromatography. J. Chromatogr. B Biomed. Appl. 686:65–75.

    Google Scholar 

  • Dumont, E., Von Bahr, C., Perry, T. L., and Bertilsson, L. (1987). Glucuronidation of the enantiomers of E-10-hydroxynortriptyline in human and rat liver microsomes. Pharmacol. Toxicol. 61:335–341.

    Google Scholar 

  • Eap, C. B., Koeb, L., Holsboer-Trachsler, E., and Baumann, P. (1992). Plasma levels of trimipramine and metabolites in four patients: Determination of the enantiomer concentrations of the hydroxy metabolites. Ther. Drug. Monit. 14:380–385.

    Google Scholar 

  • Eap, C. B., Powell, K., Campussouche, D., Monney, C., Baettig, D., Taeschner, W., and Bauman, P. (1994). Determination of the enantiomers of mianserin, desmethylmianserin, and 8-hydroxymianserin in the plasma and urine of mianserin-treated patients. Chirality 6:555–563.

    Google Scholar 

  • Eap, C. B., Gaillard, N., Powell, K., and Bauman, P. (1996a). Simultaneous determination of plasma levels of fluvoxamine and of the enantiomers of fluoxetine and norfluoxetine by gas chromatography-mass spectrometry. J. Chromatogr. B 682:265–272.

    Google Scholar 

  • Eap, C. B., Guentert, T. W., Schaublin Loidl, M., Stabl, M., Koeb, L., Powell, K., and Baumann, P. (1996b). Plasma levels of the enantiomers of thioridazine, thioridazine 2-sulfoxide, thioridazine 2-sulfone, and thioridazine 5-sulfoxide in poor and extensive metabolizers of dextromethorphan and mephenytoin. Clin. Pharmacol. Ther. 59:322–331.

    Google Scholar 

  • Eap, C. P., Powell, K., and Baumann, P. (1997) Determination of the enantiomers of mianserin and its metabolites in plasma by capillary electrophoresis after liquid-liquid extraction and on-column sample preconcentrations. J. Chromatogr. Sci. 35:315–320.

    Google Scholar 

  • Eichelbaum, M. (1992). Pharmacokinetic and pharmacodynamic consequences of stereoselective drug metabolism in man. Biochem. Pharmacol. 37:93–96.

    Google Scholar 

  • Evans, A. M. (1992). Enantioselective pharmacodynamics and pharmacokinetics of chiral non-steroidal anti-inflammatory drugs. Eur. J. Clin. Pharmacol. 42:237–256.

    Google Scholar 

  • Evans, A. M., Nation, R. H., Sansom, L. N., Bochner, F., and Somogyi, A. A (1988). Stereoselective drug disposition: Potential for misinterpretation of drug disposition data. Br. J. Clin. Pharmacol. 26:771–780.

    Google Scholar 

  • Fassihi, A. R. (1993). Racemates and enantiomers in drug development. Int. J. Pharmacol. 92:1–14.

    Google Scholar 

  • Fava, M. M., Rappe, S. M., Pava, J. A., Nierenberg, A. A., Alpert, J. E., and Rosenbaum, J. F. (1995). Relapse in patients on long-term fluoxetine treatment: Response to increased fluoxetine dose. J. Clin. Psychiatry. 56:52–55.

    Google Scholar 

  • Fernandez, C., Gimenez, F., Baune, B., and Maradeix, V. (1993a). Determination of the enantiomers of zopiclone and its two chiral metabolites in urine using an automated coupled achiral chiral chromatographic system. J. Chromatogr. 617:271–278.

    Google Scholar 

  • Fernandez, C., Maradeix, V., Gimenez, F., Thuillier, A., and Farinotti, R. (1993b). Pharmacokinetics of zopiclone and its enantiomers in caucasian young healthy volunteers. Drug Metab. Dispos. 21:1125–1128.

    Google Scholar 

  • Fowler, J. S., MacGregor, R. R., Wolf, A. P., Arenett, C. D., Dewey, S. L., Schyler, D., et al. (1987). Mapping human brain monoamine oxidase A and B with 11C-labeled suicide inactivators and PET. Science 235:481–485.

    Google Scholar 

  • Fuentes, J. A., Oleshansky, M. A., and Neff, N. H (1976). Comparison of the apparent antidepressant activity of (+)-and (−)-tranylcypromine in an animal model. Biochem. Pharmacol. 25:801–804.

    Google Scholar 

  • Fuller, R. W., Snoddy, H. D., Krushinski, J. H., and Robertson, D. W. (1992). Comparison of norfluoxetine enantiomers as serotonin uptake inhibitors in vivo. Neuropsychopharmacology 31:997–1000.

    Google Scholar 

  • Gerlach, M., Youdim, M. B. H., and Riederer, P. (1996). Pharmacology of selegiline. Neurology 47(Suppl. 3):S137-S145.

    Google Scholar 

  • Gibaldi, M. (1993). Stereoselective and isozyme-selective drug interactions. Chirality 5:407–413.

    Google Scholar 

  • Goodnick, P. J. (1991). Pharmacokinetics of second generation antidepressants: Bupropion. Psychopharmacol. Bull. 27:513–519.

    Google Scholar 

  • Goodnough, D. B., and Baker, G. B. (1994). 5-Hydroxytryptamine2 and beta-adrenergic receptor regulation in rat brain following chronic treatment with desipramine and fluoxetine alone and in combination. J. Neurochem. 62:2262–2268.

    Google Scholar 

  • Görög, S., and Gazdag, M. (1994). Enantiomeric derivatization for biomedical chromatography. J. Chromatogr. 659:51–84.

    Google Scholar 

  • Grace, J. M., Kinter, M. T., and Macdonald, T. L. (1994). Atypical metabolism of deprenyl and its enantiomer, (S)-(+)-N,α-dimethyl-N-propynylphenethylamine, by cytochrome P450 2D6. Chem. Res. Toxicol. 7:286–290.

    Google Scholar 

  • Gram, L. F. (1994). Fluoxetine. N. Engl. J. Med. 331:1354–61.

    Google Scholar 

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

    Google Scholar 

  • Hampson, D. R., Baker, G. B., and Coutts, R. T. (1986). A comparison of the neurochemical properties of the stereoisomers of tranylcypromine in the central nervous system. Cell. Mol. Biol. 32:593–599.

    Google Scholar 

  • Hand, T. H., Marek, G. J., and Seiden, L. S. (1991). Comparison of the effects of mianserin and its enantiomers and metabolites on a behavioral screen for antidepressant activity. Psychopharmacology 105:453–458.

    Google Scholar 

  • Haupt, D. (1997) Determination of citalopram enantiomers in human plasma by liquid chromatographic separation on a chiral-AGP column. J. Chromatogr. B Biomed. Appl. 685:299–305.

    Google Scholar 

  • Heinig, R., and Blaschke, G. (1993). In vivo and in vitro stereoselective metabolism of mianserin in mice. Arzneimittelforschung 43:5–10.

    Google Scholar 

  • Heinig, R., Delbressine, L. P., Kaspersen, F. M., and Blaschke, G. (1993). Enantiomeric aspects of the metabolism of mianserin in rats. Arzneimittelforschung 43:709–715.

    Google Scholar 

  • Hempel, G., and Blaschke, G. (1996). Enantioselective determination of zopiclone and its metabolites in urine by capillary electrophoresis. J. Chromatogr. B Bio Med Appl. 675:139–146.

    Google Scholar 

  • Hobbs, D. C. (1969). Distribution and metabolism of doxepine. Biochem. Pharmacol. 18:1941–1954.

    Google Scholar 

  • Horn, A. S., and Snyder, S. H. (1972). Steric requirements for catecholamine uptake by rat brain synaptosomes: Studies with rigid analogs of amphetamine. J. Pharmacol. Exp. Ther. 180:523–530.

    Google Scholar 

  • Hrdina, P. D., Bakish, D., Swenson, S., and Lapierre Y. D. (1990). Cis-and trans-isomers of deoxepin and desmethyldoxepin in the plasma of depressed patients treated with doxepin. Ther. Drug Monit. 12:129–133.

    Google Scholar 

  • Hutt, A. J., and Tan, S. C. (1996). Drug chirality and its clinical significance. Drugs 52:1–12.

    Google Scholar 

  • Hutt, A. J., Hadley, M. R., and Tan, S. C. (1994). Enantiospecific analysis: Applications in bioanalysis and metabolism. Eur. J. Drug Metab. Pharmacokin. 19:241–251.

    Google Scholar 

  • Hyttel, J., Bogeso, K. P., Perregaard, J., and Sanchez, C. (1992). The pharmacological effect of citalopram residues in the (S)-(+)-enantiomer. J. Neural. Transm. 88:157–160.

    Google Scholar 

  • Jamali, F., Mahvar, R., and Pasutto, F. M. (1989). Enantioselective aspects of drug action and disposition: therapeutic pitfalls. J. Pharm. Sci. 78:695–715.

    Google Scholar 

  • Jancsar, S. M., and Leonard, B. E. (1984). The effect of (+/−)mianserin and its enantiomers on the behavioural hyperactivity of the olfactory-bulbectomized rat. Neuropharmacology 23:1065–1070.

    Google Scholar 

  • Jortani, S. A., and Poklis, A. (1993). Determination of thioridazine enantiomers in human serum by sequential achiral and chiral high-performance liquid chromatography. J. Anal. Toxicol. 17:374–377.

    Google Scholar 

  • Kaiser, C., and Setler, P. E. (1981). Antipsychotic agents. In Wolff, M. E. (ed.), Burger's Medicinal Chemistry, Part III, 4th ed., John Wiley and Sons, New York, p. 859.

    Google Scholar 

  • Kooyman, A. R., Zwart, R., Vanderheijden, P. M., Van-Hooft, J. A., and Vijverberg, H. P. (1994). Interaction between enantiomers of mianserin and ORG3770 at 5-HT3 receptors in cultured mouse neuroblastoma cells. Neuropharmacology 33:501–507.

    Google Scholar 

  • Koyama, E., Chiba, K., Tani, M., and Ishizaki, T. (1996). Identification of human cytochrome P450 isoforms involved in the stereoselective metabolism of mianserin enantiomers. J. Pharmacol. Exp. Ther. 278:21–30.

    Google Scholar 

  • Kunze, K. L., Eddy, A. C., Gibaldi, M., and Trager, W. F. (1991). Metabolic enantiomeric interactions: The inhibition of human (S) warfarin-7-hydroxylase by (R) warfarin. Chirality 3:24–29.

    Google Scholar 

  • Laizure, S. C., De Vane, C. L., Stewart, J. T., Dommisse, C. S., and Lai, A. A. (1985). Pharmacokinetics of bupropion and its major basic metabolites in normal subjects after a single dose. Clin. Pharmacol. Ther. 38:586–589.

    Google Scholar 

  • Lavoie, P.-A., Beuachamp, G., and Elie, R. (1994). Absence of stereoselectivity of some tricyclic antidepressants for the inhibition of depolarization-induced calcium uptake in rat cingulate cortex synaptosomes. J. Psychiatr. Neurosci. 19:208

    Google Scholar 

  • Lee, E. J. D., and Williams, K. M. (1990). Chirality: Clinical pharmacokinetic and pharmacodynamic considerations. Clin. Pharmacokinet. 18:339–345.

    Google Scholar 

  • Lee, S. K-S., Baker, G. B., and Coutts, R. T. (1995) Simultaneous determination of the enantiomers of trimipramine by high pressure liquid chroamtography (HPLC): Application to rat tissue samples. Proc. 18th Annu. Meet. Can. Coll. Neuropsychopharmacol., Vancouver, BC.

  • Magyar, K., and Tothfalusi, L. (1984). Pharmacokinetic aspects of deprenyl effects. Pol. J. Pharmacol. Pharm. 36:373–384.

    Google Scholar 

  • Magyar, K., Vizi, E. S., and Esceri, Z. (1967). Comparative pharmacological analysis of the optical isomers of phenyl-isopropyl-methylpropinylamine (E250). Acta Physiol. Hung. 32:377–387.

    Google Scholar 

  • Maura, G., Gemignani, A., and Raiteri, M. (1985). Alpha 2-adrenoceptors in rat hypothalamus and cerebral cortex: Functional evidence for pharmacologically distinct subpopulations. Eur. J. Pharmacol. 116:335–339.

    Google Scholar 

  • Medical Economics Data (1995). Luvox (fluvoxamine maleate). In Physicians Desk Reference, 49th ed., Medical Economics Data Production Co., Montvale, NJ, Suppl. A, pp. 44–47.

    Google Scholar 

  • Mehvar, R., and Jamali, F. (1997). Bioequivalence of chiral drugs. Stereospecific versus non-stereospecific methods. Clin. Pharmacokinet. 33:122–141.

    Google Scholar 

  • Mendlewicz, J. (1995). Pharmacologic profile and efficacy of venlafaxine. Int. Clin. Psychopharmacol. 2:5–13.

    Google Scholar 

  • Midha, K. K., Hubbard, J. W., McKay, G., Hawes, E. M., Korchinski, E. D., Gurnsey, T., Cooper, J. K., and Schwede, R. (1992). Stereoselective pharmacokinetics of doxepin isomers. Eur. J. Clin. Pharmacol. 42:539–544.

    Google Scholar 

  • Muller, W. E., and Wollert, U. (1975). High stereospecificity of the benzodiazepine binding site on human albumin. Studies with d-and l-oxazepam hemisuccinate. Mol. Pharmacol. 11:52–60.

    Google Scholar 

  • Mutschler, E., Gietl, Y., Krauss, D., Martin, E., Pflugmann, G., and Weber, H. (1990). Stereospecific analysis and human pharmacokinetics of the enantiomers of drugs administered as racemates. In Holmstedt, B., Frank, H. and Testa, B. (eds.), Chirality and Biological Activity, Alan R. Liss, New York, pp. 199–219.

    Google Scholar 

  • Nation, R. L. (1994). Chirality in new drug development: Clinical pharmacokinetic considerations. Clin. Pharmacokinet. 27:249–255.

    Google Scholar 

  • Nerurkar, S. G., Dighe, S. V., and Williams, R. L. (1992). Bioequivalence of racemic drugs. J. Clin. Pharmcol. 32:935–943.

    Google Scholar 

  • Nickolson, V. J., and Pinder, R. M. (1984). In Smith, D. F. (ed.), Handbook of Stereoisomers: Drugs in Psychopharmacology, CRC Press, Boca Raton, FL, pp. 215–240.

    Google Scholar 

  • Nordin, C., and Bertilsson, L. (1995). Active hydroxymetabolites of antidepressants. Clin. Pharmacokinet. 28:26–40.

    Google Scholar 

  • Nusser, E., Nill, K., and Breyer-Paff, U. (1988). Enantioselective formation and disposition of (E)-and (Z)-10-hydroxynortriptyline. Drug Metab. Dispos. 16:509–511.

    Google Scholar 

  • Otton, S. V., Ball, S. E., Cheung, S. W., Inaba, T., Rudolph, R. L., and Sellers, E. M. (1996). Venlafaxine oxidation in vitro is catalysed by CYP2D6. Br. J. Clin. Pharmacol. 41:149–156.

    Google Scholar 

  • Peet, M., and Behagel, H. (1978). Mianserin: a decade of scientific development. Br. J. Clin. Pharmacol. 5:5S-9S.

    Google Scholar 

  • Pichini, S., Pacifici, R., Altieri, I., Pellegrini, M., and Zuccaro, P. (1996). Stereoselective determination of fluoxetine and nofluoxetine enantiomers in plasma samples by high pressure liquid chromatography. J. Liq. Chromatogr. Rel. Technol. 19:1927–1935.

    Google Scholar 

  • Pinder, R. M. (1985). Adrenoreceptor interactions of the enantiomers and metabolites of mianserin: Are they responsible for the antidepressant effect? Acta Psychiatr. Scand. Suppl. 320:1–9.

    Google Scholar 

  • Pinder, R. M., and van Delft, A. M. (1983a). Pharmacological aspects of mianserin. Acta Psychiatr. Scand. Suppl. 302:59–71.

    Google Scholar 

  • Pinder, R. M., and van Delft, A. M. L. (1983b). The potential therapeutic role of the enantiomers and metabolites of mianserin. Br. J. Clin. Pharmacol. 15:269S-276S.

    Google Scholar 

  • Pinder, R. M., Brogden, R. N., Speight, T. M., and Avery, G. S. (1977). Doxepin up-to-date: A review of its pharmacological properties and therapeutic efficacy with particular reference to depression. Drugs 13:161–218.

    Google Scholar 

  • Posner, J., Bye, A., Dean, K., Peck, A. W., and Whiteman, P. D. (1985). The disposition of bupropion and its metabolites in healthy male volunteers after single and multiple doses. Eur. J. Clin. Pharmacol. 29:97–103.

    Google Scholar 

  • Potts, B. D., and Parli, C. J. (1992). Analysis of the enantiomers of fluoxetine and norfluoxetine in plasma and tissue using chiral derivatization and normal-phase liquid chromotography. J. Liq. Chromatogr. 15:665–681.

    Google Scholar 

  • Raiteri, M., Maura, G., and Versace, P. (1983). Functional evidence for two stereochemically different alpha-2 adrenoceptors regulating central norepinephrine and serotonin release. J. Pharmacol. Exp. Ther. 224:679–684.

    Google Scholar 

  • Rauws, A. G., and Groen, K. (1994). Current regulatory (draft) guidance on chiral medicinal products: Canada, EEC, Japan, United States. Chirality 6:72–75.

    Google Scholar 

  • Reynolds, G. P., Elsworth, J. D., Blau, K., Sandler, M., Lees, A. J., and Stern, G. M (1978). Deprenyl is metabolized to methylamphetamine and amphetamine in man. Br. J. Clin. Pharmacol. 6:542–544.

    Google Scholar 

  • Reynolds, G. P., and Riederer, P. (1981). Tranylcypromine isomers in the treatment of Parkinson's disease: Biochemical effects. Int. Pharmacopsychiat 16:30–33.

    Google Scholar 

  • Reynolds, J. E. F. (ed.) (1982). Martindale: The Extra Pharmacopeia, 28th ed., Pharmceutical Press, London, p 133.

    Google Scholar 

  • Rochat, B., Amery, M., and Bauman, P. (1995). Analysis of enantiomers of citalopram and its demethylated metabolites in plasma of depressive patients using chiral reverse-phase liquid chromatography. Ther. Drug. Monitor. 17:273–279.

    Google Scholar 

  • Rosseel, M. T., Bogaert, M. G., and Claeys, M. (1978). Quantitative GLC determination of cis-and trans-isomers of doxepin and desmethyldoxepin. J. Pharm. Sci. 67:802–805.

    Google Scholar 

  • Ruelius, H. W., Tio, C. O., Knowles, J. A., McHugh, S. L., Schilling, R. T., and Sisenwine, S. F. (1979). Diastereoisomeric glucuronides of oxazepam: Isolation and stereoselective enzymic hydrolysis. Drug Metab. Dispos. 7:40–43.

    Google Scholar 

  • Salama, A., and Mueller-Eckhardt., C. (1985). The role of metabolite-specific antibodies in nomifensine-dependent immune hemolytic anemia. N. Engl. J. Med. 313:469–474.

    Google Scholar 

  • Schoemaker, H., Berendsen, H. H., Stevens, H. J., and Nickolson, V. J. (1981). Differences in presynaptic alpha-blockade, noradrenaline uptake inhibition, and potential antidepressant activity between (+)-and (−)mianserin. Psychopharmacology 74:137–142.

    Google Scholar 

  • Schurig, V. (1994). Enantiomer separation by gas chromatography on chiral stationary phases. J. Chromatog. 666:111–129.

    Google Scholar 

  • Settle, E. C., and Ayd, F. J. (1980). Trimipramine: Twenty years' worldwide clinical experience. J. Clin. Psychiat. 41:266–274.

    Google Scholar 

  • Sidhu, J., Priskorn, M., Powlsen, M., Segonzac, A., Grollier, G., and Larsen, M. (1997). Steady-state pharmacokinetics of the enantiomers of citalopram and its metabolites in humans. Chirality 9:686–692.

    Google Scholar 

  • Sisenwine, S. F., Tio, C. O., Hadley, F. V., Liu, A. L., Kimmmel, H. B., and Ruelius, H. W. (1982). Species-related differences in the stereoselective glucuronidation of oxazepam. Drug Metab. Dispos. 10:605–608.

    Google Scholar 

  • Sjöqvist, F., Alenxanderson, B., Ashberg, M., Bertilsson, L., Borga, O., Hamberger, B., and Tuck, D. (1979). Pharmacokinetics and biological effects of nortriptyline in man. Acta Pharmacol. Toxicol. 29(Suppl. 3):255–280.

    Google Scholar 

  • Smith, D. F. (1984). CRC Handbook of Stereoisomers: Drugs in Psychopharmacology, CRC Press, Boca Raton, FL.

    Google Scholar 

  • Spahn-Langguth, H., Hahn, G., Mutschler, E., Mohrke, W., and Langguth, P. (1992). Enantiospecific high-performance liquid chromatographic assay with fluorescence detection for the monoamine oxidase inhibitor tranylcypromine and its applicability in pharmacokinetic studies. J. Chromatogr. Biomed. Appl. 584:229–237.

    Google Scholar 

  • Srinivas, N. R., Shyu, W. C., and Barbhaiya, R. H. (1995). Gas chromatographic determination of enantiomers as diastereomers following pre-column derivatization and applications to pharmacokinetic studies: A review. Biomed. Chromatogr. 9:1–9.

    Google Scholar 

  • Stevens, J. C., and Wrighton, S. A. (1993). Interaction of the enantiomers of fluoxetine and norfluoxetine with human liver cytochromes P450. J. Pharmacol. Exp. Ther. 266:964–971.

    Google Scholar 

  • Šubert, J. (1994). Progress in the separation of enantiomers of chiral drugs by HPLC without their prior derivatization. Pharmazie 49:3–13.

    Google Scholar 

  • Svendsson, C. N., Froimowitz, M., Hrbek, C., Campbell, A., Kula, N., Baldessarini, R. J., Cohan, B. M., Teicher, M. H., and Bird, E.D. (1988). Receptor affinity, neurochemistry and behavioral characteristics of the enantiomers of thioridazine: Evidence for different stereoselectives at D1 and D2 receptors in rat brain. Neuropharmacology 27:1117–1124.

    Google Scholar 

  • Terabe, S., Otsuka, K., and Nishi, H. (1994). Separation of enantiomers by capillary electrophoretic techniques. J. Chromatogr. A 666:295–319.

    Google Scholar 

  • Testa, B. (1986). Chiral aspects of drug metabolism. Trends Pharmacol. Sci. 7:60–64.

    Google Scholar 

  • Torok-Both, G. A., Baker, G. B., Coutts, R. T., McKenna, K. F., and Aspeslet, L. J. (1992). Simultaneous determination of fluoxetine and norfluoxetine enantiomers in biological samples by gas chromatography with electroncapture detection. J. Chromatogr. 579:99–106.

    Google Scholar 

  • Tucker, G. T., and Lennard, M. S. (1990). Enantiomer specific pharmacokinetics. Pharmacol. Ther. 45:309–329.

    Google Scholar 

  • Tybring, G., Otani, K., Kaneko, S., Mihara, K., Fukushima, and Bertilsson, L. (1995). Enantioselective determination of mianserin and its desmethyl metabolite in plasma during treatment of depressed Japanese patients. Ther. Drug Monit. 17:516–521.

    Google Scholar 

  • Van Harten, J. (1993). Clinical pharmacokinetics of selective serotonin reuptake inhibitors. Clin. Pharmacokinet. 24:203–220.

    Google Scholar 

  • Vespalec, R., and Bocek, P. (1994). Chiral state of the art. Electrophoresis 15:755–762

    Google Scholar 

  • von Bahr, C., Movin, G., Nordin, C., Liden, A., Hammarlund-Udenaes, M., Hedberg, A., Ring, H., and Sjoqvist, F. (1991). Plasma levels of thioridazine and metabolites are influenced by the debrisoquin hydroxylation phenotype. Clin. Pharmacol. Ther. 49:234–239.

    Google Scholar 

  • Weber-Grandke, H., Hahn, G., Mutschler, E., Möhrke, W., Langguth, P., and Spahn-Langguth, H. (1993). The pharmacokinetics of tranylcypromine enantiomers in healthy subjects after oral administration of racemic drug and the single enantiomers. Br. J. Clin. Pharmacol. 36:363–365.

    Google Scholar 

  • Wong, D. T., Fuller, R. W., and Robertson, D. W. (1990). Fluoxetine and its two enantiomers as selective serotonin uptake inhibitors. Acta Pharma. Nordica 2:171–179.

    Google Scholar 

  • Wong, D. T., Bymaster, F. P., Reid, L. R., Mayle, D. A., Krushinski, J. H., and Robertson D. W. (1993). Norfluoxetine enantiomers as inhibitors of serotonin uptake in rat brain. Neuropsychopharmacology 8:337–344.

    Google Scholar 

  • Wong, D. T., Bymaster, F. P., and Engleman, E. A. (1995) Prozac (fluoxetine, Lilly 110140), the first selective serotonin uptake inhibitor and an antidepressant drug: Twenty years since its first publication. Life Sci. 57:411–441.

    Google Scholar 

  • Wood, M. D., Thomas, D. R., Watkins, C. J., and Newberry, N. R. (1993). Stereoselective interaction of mianserin with 5-HT3 receptors. J. Pharm. Pharmacol. 45:711–714.

    Google Scholar 

  • Yang, S. K., and Lu, X. L. (1989). Racemization kinetics of enantionmeric oxazepams and stereoselective hydrolysis of enantiomeric oxazepam 3-acetates in rat liver microsomes and brain homogenate. J. Pharm. Sci. 78:789–795.

    Google Scholar 

  • Yang, S. K., and Lu X.-L. (1992). Resolution and stability of oxazepam enantiomers. Chirality 4:443–446.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Pfizer Inc., 235 East 42nd Street, New York, New York, 10017-5755

    Roger M. Lane

  2. Neurochemical Research Unit Department, Psychiatry Mackenzie Centre, University of Alberta, Edmonton, Alberta, T6G 2B7, Canada

    Glen B. Baker

Authors
  1. Roger M. Lane
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Glen B. Baker
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lane, R.M., Baker, G.B. Chirality and Drugs Used in Psychiatry: Nice to Know or Need to Know?. Cell Mol Neurobiol 19, 355–372 (1999). https://doi.org/10.1023/A:1006997731966

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1006997731966

Search

Navigation