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Pharmacy World and Science

, Volume 15, Issue 5, pp 186–192 | Cite as

Terfenadine: A mixture of equipotent antihistamine enantiomers without a clear ‘isomeric ballast’

  • Ming-Qiang Zhang
  • Henk Timmerman
Reviews

Abstract

Terfenadine was the first non-sedating histamine H1 receptor antagonist and one of the most frequently prescribed H1 antihistamines. Terfenadine has one asymmetric centre in the molecule and is currently used as a racemate. Different methods and approaches for obtaining pure enantiomers of terfenadine are summarized and discussed in the present paper. Studies on antihistamine activity of the enantiomers, their side-effects on the central nervous system, calcium channel affinity and metabolism are also reviewed and analysed.

Keywords

Adverse effects Calcium channels Histamine H1 receptor blockaders Metabolism Receptors, histamine H1 Resolution Stereoisomers Synthesis Terfenadine 

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References

  1. 1.
    Carr AA, Meyer DR. Synthesis of terfenadine. Arzneimittelforschung/Drug Res 1982;32:1157–9.Google Scholar
  2. 2.
    Kinsolving CR, Munro NL, Carr AA. Separation of the CNS and H1 receptor effects of antihistamine agents. Pharmacologist 1973;15:221.Google Scholar
  3. 3.
    McTavish D, Goa KL, Ferrill M. Terfenadine: an updated review of its pharmacological properties and therapeutic efficacy. Drugs 1990;39:552–74.PubMedGoogle Scholar
  4. 4.
    Makino S, Ikemori R, Fukuda T, Miyamoto T, Suzuki S. Clinical evaluation of terfenadine in bronchial asthma —comparison with ketotifen in a multi-center double-blind study. Rinsho lyaku 1988;4:1687–722.Google Scholar
  5. 5.
    Rafferty P, Jackson L, Smith R, Holgate ST. Terfenadine in the treatment of grass pollen sensitive asthmatics during the hay fever season. Br J Clin Pharmacol 1988;25:623p-4p.Google Scholar
  6. 6.
    Terhechte A, Blaschke G. Indirekte und direkte Racemattrennung von Terfenadin und seinem Hauptmetaboliten MDL16,455A. Arch Pharm 1991;324:710.Google Scholar
  7. 7.
    Weems H, Zamani K. Resolution of terfenadine enantiomers byβ-cyclodextrin chiral stationary phase high-performance liquid chromatography. Chirality 1992;4:268–72.PubMedGoogle Scholar
  8. 8.
    Chan KY, George RC, Chen TM, Okerholm RA. Direct enantiomeric separation of terfenadine and its major acid metabolite by high-performance liquid chromatography, and the lack of stereoselective terfenadine enantiomer biotransformation in man. J Chromatogr 1991;571:291–7.PubMedGoogle Scholar
  9. 9.
    Leysen JE, Gommeren W, Janssen PFM, Janssen PAJ. Comparative study of central and peripheral histamine H1 receptor bindingin vitro andex vivo of non-sedating antihistamines and of noberastine, a new agent. Drug Dev Res 1991;22:165–78.Google Scholar
  10. 10.
    Zhang MQ, Ter Laak AM, Timmerman H. Optical isomers of the H1 antihistamine terfenadine: synthesis and activity. Bioorg Med Chem Lett 1991;1:387–90.Google Scholar
  11. 11.
    Zamani K, Conner DP, Weems HB, Yang SK, Cantilena LR Jr. Enantiomeric analysis of terfenadine in rat plasma by HPLC. Chirality 1991;3:467–70.PubMedGoogle Scholar
  12. 12.
    Brown HC, Chandrasekharan J, Ramachandran PV. Chiral synthesis via organoboranes 14. Selective reductions 41. Diisopinocampheylchloroborane, an exceptionally efficient chiral reducing agent. J Am Chem Soc 1988;110:l539–46.Google Scholar
  13. 13.
    Zhang MQ, Ter Laak AM, Timmerman H. Structure-activity relationships within a series of analogues of the histamine H1 antagonist terfenadine. Eur J Med Chem 1993;28:165–73.Google Scholar
  14. 14.
    Moragues J, Roberts DJ. Ebastine. Drugs Future 1990;15: 674–9.Google Scholar
  15. 15.
    Ter Laak AM, Donne-op-Denkelder GM, Bast A, Timmerman H. Is there a difference in the affinity of histamine H1-receptor antagonists for CNS and peripheral receptors? Anin vitro study. Eur J Pharmacol 1993;232:199–205.PubMedGoogle Scholar
  16. 16.
    Rose C, Quach TT, Llorens C, Schwartz JC. Relationship between occupation of cerebral H1-receptors and sedative properties of antihistamines. Arzneimittelforschung/Drug Res 1982;32:1171–3.Google Scholar
  17. 17.
    Tasaka K, Kamei C, Tsujimoto S, Chung YH. Influence of the optical isomers of terfenadine on EEG spectral powers in conscious rats. Oyo Yakuri 1989;38:489–93.Google Scholar
  18. 18.
    Audus KL, Chikhale PJ, Miller DW, Thompson SE, Borchardt RT. Brain uptake of drugs: the influence of chemical and biological factors. In: Testa B, editor. Advances in drug research. Vol. 23. London: Academic Press, 1992:3–66.Google Scholar
  19. 19.
    Young RC, Mitchell RC, Brown TH, Ganellin CR, Griffiths R, Jones M, et al. Development of a new physicochemical model for brain penetration and its application to the design of centrally acting H2 receptor histamine antagonists. J Med Chem 1988;31:656–71.PubMedGoogle Scholar
  20. 20.
    Chen TM, Chan KY, Coutant JE, Okerholm RA. Determination of the metabolites of terfenadine in human urine by thermospray liquid chromatograpy-mass spectrometry. J Pharm Biomed Anal 1991;9:929–33.PubMedGoogle Scholar
  21. 21.
    Monahan BP, Ferguson CL, Killeavy ES, Lloyd BK, Cantilena LR Jr. Torsade de pointes occurring in association with terfenadine use. JAMA 1990;264:2788–90.PubMedGoogle Scholar
  22. 22.
    Zimmermann M, Duruz H, Guinand O, Broccard O, Levy P, Lacatis D, et al. Torsades de pointes after treatment with terfenadine and ketoconazole. Eur Heart J 1992, 13:1002–3.PubMedGoogle Scholar
  23. 23.
    Trager WF, Jones JP. Stereochemical consideration in drug metabolism. In: Bridges JW, Chasseaud LF, Gibson GG, editors. Progress in drug metabolism. Vol. 10. London: Taylor & Francis, 1987:55–84.Google Scholar
  24. 24.
    Tasaka K, Akagi M, Mio M, Okamoto M, Miyoshi K, Deishi K. Antiallergic effects of terfenadine on immediate type hyper-sensitivity reactions and the mechanisms of those actions. Yakuri to Chiryo 1988;16:2465–80.Google Scholar
  25. 25.
    Foreman JC, Rihoux JP. The antiallergic activity of H1 histamine receptor antagonists in relation to their actions on cell calcium. In: Church MK, Rihoux JP, editors. Therapeutic index of antihistamines. Lewiston: Hogrefe & Huber Publishers, 1992:32–46.Google Scholar
  26. 26.
    Zhang MQ, Caldirola P, Timmerman H. Calcium antagonism and structure-affinity relationships of terfenadine, a histamine H1 antagonist, and some related compounds. J Pharm Pharmacol 1993;45:63–6.PubMedGoogle Scholar
  27. 27.
    Zhang MQ, Caldirola P, Timmerman H. Chiral manipulation of drug selectivity: studies on a series of terfenadine-derived dual antagonists on H1-receptors and calcium channels. Agents Actions. In press.Google Scholar
  28. 28.
    Zhang MQ, Caldirola P, Leysen DC, Timmerman H. Novel stereoselective calcium channel ligands of the diphenylalkylamine-type. Bioorg Med Chem Lett 1992;2:1283–8.Google Scholar
  29. 29.
    Kannan MS, Davis C. Mode of action of calcium antagonists on responses to spasmogens and antigen challenge in human airway smooth muscle. Respir Physiol 1988;74:15–24.PubMedGoogle Scholar
  30. 30.
    Ariëns EJ. Stereochemistry, a basis for sophisticated nonsense in pharmacokinetics and clinical pharmacology. Eur J Clin Pharmacol 1984;26:663–8.PubMedGoogle Scholar

Copyright information

© Periodicals Service Company 1993

Authors and Affiliations

  • Ming-Qiang Zhang
    • 1
  • Henk Timmerman
    • 1
  1. 1.Department of PharmacochemistryFree UniversityHV Amsterdamthe Netherlands

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