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Great Expectations in Stereochemistry: Focus on Antidepressants

Published online by Cambridge University Press:  07 November 2014

C. Lindsay DeVane  and
David W. Boulton
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Abstract

Chirality has become an increasingly important consideration in the development of psychoactive drugs because enantiomers often show major differences in their pharmacokinetic and pharmacologic properties. This review illustrates the implications of stereochemistry in clinical psychopharmacology using the antidepressant class of drugs as a focus. In many cases, a better understanding of stereochemistry can improve therapeutic outcomes. For example, with citalopram, the racemic formulation is effective for depression as well as panic and obsessive-compulsive disorders. However, the S-enantiomer, escitalopram, is at least twice as potent as racemic citalopram as an inhibitor of serotonin reuptake, implying that it can be used at lower doses, while offering an improved therapeutic index as well as an improved safety profile and reduced drug interaction liability. Clinical trial data support these advantages. Continuing research on the stereochemical properties of psychoactive drugs should simplify the characterization of dose-response relationships, and clarify the effects of disease states, genetic polymorphisms, pregnancy, age, and gender on stereoselective pharmacokinetics and pharmacodynamics. Better understanding of the fate of chiral psychotropic agents and the factors that influence their stereoselective disposition and actions will provide a rational basis for their expanded use in various patient populations.

Type
Research Article
Information
CNS Spectrums , Volume 7 , Issue S1: The Biological and Clinical Significance of Single Isomers , April 2002 , pp. 28 - 33
Copyright
Copyright © Cambridge University Press 2002

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References

REFERENCES

1.Boulton, DW, DeVane, CL. Development and application of a chiral high pressure liquid chromatography assay for pharmacokinetic studies of methadone. Chirality. 2000;2:681–687.3.0.CO;2-J>CrossRefGoogle Scholar
2.Boulton, DW, Arnaud, P, DeVane, CL. Pharmacokinetics and pharmacodynamics of methadone enantiomers in normal female volunteers following a single oral dose of racemate. Clin Pharmacol Ther. 2001;70:48–57.CrossRefGoogle Scholar
3.Tuomisto, J, Smith, DF. Effects of tranylcypromine enantiomers on monoamine uptake and release and imipramine binding. J Neural Transm. 1986;65:135–145.CrossRefGoogle ScholarPubMed
4.Aboul-Enein, HY, Serignese, V. Direct separation of tranylcypromine enantiomers and their profile in an atypical depressive patient. Biomed Chromatogr. 1995;9:98–101.CrossRefGoogle Scholar
5.Spahn-Langguth, H, Hahn, G, Mutschler, E, Mohrke, W, Langguth, P. Enantiospecific high-performance liquid chromatographic assay with fluorescence detection for the monoamine oxidase inhibitor tranylcypromine and its applicability in pharmacokinetic studies. J Chromatogr. 1992;584:229–237.CrossRefGoogle ScholarPubMed
6.Gross, G, Xin, X, Gastpar, M. Trimipramine: pharmacological reevaluation and comparison with clozapine. Neuropharmacology. 1991;30:1159–1166.CrossRefGoogle ScholarPubMed
7.Eap, CB, Bender, S, Gastpar, M, et al.Steady state plasma levels of the enantiomers of trimipramine and of its metabolites in CYP 2D6-, CYP 2C19- and CYP 3A4/5-phenotyped patients. Ther Drug Monit. 2000;22:209–214.CrossRefGoogle Scholar
8.Musso, DL, Mehta, NB, Soroko, FE, Ferris, RM, Hollingsworth, EB, Kenney, BT. Synthesis and evaluation of the antidepressant activity of the enantiomers of bupropion. Chirality. 1993;5:495–500.CrossRefGoogle ScholarPubMed
9.Martin, P, Massol, J, Colin, JN, LaComblez, L, Puech, AJ. Antidepressant profile of bupropion and three metabolites in mice. Pharmacopsychiatry. 1990;23:187–194.CrossRefGoogle ScholarPubMed
10.Suckow, RF, Zhang, MF, Cooper, TB. Enantiomeric determination of the phenylmorpholinol metabolite of bupropion in human plasma using coupled achiral-chiral liquid chromatography. Biomed Chromatogr. 1997;11:174–179.3.0.CO;2-E>CrossRefGoogle ScholarPubMed
11.Otton, SV, Ball, SE, Cheung, SW, Inaba, T, Rudolph, RL, Sellers, EM. Venlafaxine oxidation in vitro is catalysed by CYP 2D6. Br J Clin Pharmacol. 1996;41:149–156.CrossRefGoogle Scholar
12.Fogelman, SM. Schmider, J, Venkatakrishnan, K, et al.O- and N-demethylation of venlafaxine in vitro by human liver microsomes and by microsomes from cDNA-transfected cells: effect of metabolic inhibitors and SSRI antidepressants. Neuropsychopharmacology. 1999;20:480–490.CrossRefGoogle ScholarPubMed
13.Klamerus, KJ, Maloney, K, Rudolph, RL, Sisenwine, SF, Jusko, WJ, Chiang, ST. Introduction of a composite parameter to the pharmacokinetics of venlafaxine and its active O-desmethyl metabolite. J Clin Pharmacol. 1992;32:716–724.CrossRefGoogle Scholar
14.Wang, CP, Howell, SR, Scatina, J, Sisenwine, SF. The disposition of venlafaxine enantiomers in dogs, rats, and humans receiving venlafaxine. Chirality. 1992;4:84–90.CrossRefGoogle ScholarPubMed
15.Eap, CB, Bertel-Laubscher, R, Zullino, D, Amey, M, Baumann, P. Marked increase of venlafaxine enantiomer concentrations as a consequence of metabolic interactions: a case report. Pharmacopsychiatry. 2000;33:112–115.CrossRefGoogle ScholarPubMed
16.Veefkind, AH, Haffmans, PM, Hoencamp, E. Venlafaxine serum levels and CYP 2D6 genotype. Ther Drug Monit. 2000;22:202–208.CrossRefGoogle Scholar
17.Strolin-Benedetti, M, Frigerio, E, Tocchetti, P, et al.Stereoselective and species-dependent kinetics of reboxetine in mouse and rat. Chirality. 1995;7:285–289.CrossRefGoogle ScholarPubMed
18.Fleishaker, JC, Mucci, M, Pellizzoni, C, Poggesi, I. Absolute bioavailability of reboxetine enantiomers and effect of gender on pharmacokinetics. Biopharm Drug Dispos. 1999;20:53–57.3.0.CO;2-P>CrossRefGoogle ScholarPubMed
19.Cocchiara, G, Battaglia, R, Pevarello, P, Strolin-Benedetti, M. Comparison of the disposition and of the metabolic pattern of reboxetine, a new antidepressant, in the rat, dog, monkey and man. Eur J Drug Metab Pharmacokinet. 1991;16:231–239.CrossRefGoogle ScholarPubMed
20.Wienkers, LC, Allievi, C, Hauer, MJ, Wynalda, MA. Cytochrome P450-mediated metabolism of the individual enantiomers of the antidepressant agent reboxetine in human liver microsomes. Drug Metab Dispos. 1999;27:1334–1340.Google Scholar
21.Edwards, DM, Pellizzoni, C, Breuel, HP, et al.Pharmacokinetics of reboxetine in healthy volunteers. Single oral doses, linearity and plasma protein binding. Biopharm Drug Dispos. 1995;16:443–460.CrossRefGoogle ScholarPubMed
22.Wong, DT, Threlkeld, PG, Robertson, DW. Affinities of fluoxetine, its enantiomers, and other inhibitors of serotonin uptake for subtypes of serotonin receptors. Neuropsychopharmacology. 1991;5:43–47.Google ScholarPubMed
23.Fuller, RW, Snoddy, HD. Drug concentrations in mouse brain at pharmacologically active doses of fluoxetine enantiomers. Biochem Pharmacol. 1993;45:2355–2358.CrossRefGoogle Scholar
24.Hyttel, J, Bogeso, KP, Perregaard, J, Sanchez, C. The pharmacological effect of Citalopram residues in the (S)-(+)-enantiomer. J Neural Transm. Gen Sect. 1992;88:157–160.CrossRefGoogle ScholarPubMed
25.Stevens, JC, Wrighton, SA. Interaction of the enantiomers of fluoxetine and norfluoxetine with human liver cytochromes P450. J Pharmacol Exp Ther. 1993;266:964–971.Google ScholarPubMed
26.Margolis, JM, O'Donnell, JP, Mankowski, DC, Ekins, S, Obach, RS. (R)-, (S)-, and racemic fluoxetine N-demethylation by human cytochrome P450 enzymes. Drug Metab Dispos. 2000;28:1187–1191.Google Scholar
27.Fjordside, L, Jeppesen, U, Eap, CB, Powell, K, Baumann, F, Brosen, K. The stereoselective metabolism of fluoxetine in poor and extensive metabolizers of sparteine. Pharmacogenetics. 1999;9:55–60.CrossRefGoogle ScholarPubMed
28.Mechcatie, E. Fluoxetine isomer may hold advantages over Prozac. Clinical Psychiatry News. 1999;27:7.Google Scholar
29.Steiner, TJ, Ahmed, F, Findley, LJ, MacGregor, EA, Wilkinson, M. S-fluoxetine in the prophylaxis of migraine: a phase II double-blind randomized placebo-controlled study. Cephalalgia. 1998;18:283–286.CrossRefGoogle Scholar
30.Olesen, OV, Linnet, K. Studies on the stereoselective metabolism of Citalopram by human liver microsomes and cDNA-expressed cytochrome P450 enzymes. Pharmacology. 1999;59:298–309.CrossRefGoogle ScholarPubMed
31.Greenblatt, DJ, von Moltke, LL, Shader, RI. The S-enantiomer of Citalopram (Lu 26-054): cytochromes P450 mediating metabolism and cytochrome inhibitory effects. Abstract presented at the Annual Meeting of the American Psychiatric Association, 05 13-18, 2000, Chicago, Ill.Google Scholar
32.Rochat, B, Amey, M, Baumann, P. Analysis of enantiomers of Citalopram and its demethylated metabolites in plasma of depressive patients using chiral reverse-phase liquid chromatography. Ther Drug Monit. 1995;17:273–279.CrossRefGoogle ScholarPubMed
33.Sidhu, J, Priskorn, M, Poulsen, M, Segonzac, A, Grollier, G, Larsen, F. Steady-state pharmacokinetics of the enantiomers of Citalopram and its metabolites in humans. Chirality. 1997;9:686–692.3.0.CO;2-5>CrossRefGoogle ScholarPubMed
34.Zheng, Z, Jamour, M, Klotz, U. Stereoselective HPLC-assay for Citalopram and its metabolites. Ther Drug Monit. 2000;22:219–224.CrossRefGoogle ScholarPubMed
35.Foglia, JP, Pollock, BG, Kirshner, MA, Rosen, J, Sweet, R, Mulsant, B. Plasma levels of Citalopram enantiomers and metabolites in elderly patients. Psychopharmacol Bull. 1997;33:109–112.Google ScholarPubMed
36.De Camp, WH. The FDA perspective on the development of stereoisomers. Chirality. 1989;1:2–6.CrossRefGoogle ScholarPubMed
37.Burke, WJ. Fixed dose study of escitalopram in the treatment of depression. Abstract presented at the annual meeting of the American College of Neuropsychopharmacology, 12 10-14, 2000, San Juan, Puerto Rico.Google Scholar