European Journal of Clinical Pharmacology

, Volume 26, Issue 4, pp 463–470 | Cite as

Elucidation of the structure and receptor binding studies of the major primary, metabolite of dihydroergotamine in man

  • G. Maurer
  • W. Frick


The plasma concentrations and urinary excretion of dihydroergotamine and its metabolites have been measured after a single oral administration of 3 mg tritium-labelled drug to 6 male volunteers. The plasma level of non-volatile radioactivity declined biphasically with α- and β-phase half-lives of 2.1 h and 32.3 h, respectively. The peak plasma concentration was reached within 3.2h. Urinary excretion of total non-volatile radioactivity was low, amounting to 1.0% of the dose. The parent drug and four metabolites could be quantitated in urine and plasma samples. Metabolite 4 (8′-hydroxy-dihydroergotamine) was isolated from incubates of rat and monkey liver microsomal preparations. In human liver microsomal incubates, metabolite 4 was shown to be the primary metabolite of dihydroergotamine. In receptor binding studies performed with mammalian brain preparations, metabolite 4 had IC50-values at 6 monoaminergic binding sites similar to those of dihydroergotamine. Thus, it appears that the active principle consists at least of dihydroergotamine and its 8′-hydroxy derivative. As the concentration of metabolite 4 exceeded 5–7 times that of dihydroergotamine in urine and plasma, the bioavailability of dihydroergotamine should be reevaluated, taking into account the plasma concentrations of the parent drug and of its acitve metabolite, 8′-hydroxydihydroergotamine.

Key words

dihydroergotamine 8′-hydroxy-dihydroergotamine plasma metabolites bioavailability receptor affinity healthy volunteers liver microsomal incubates 


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  1. 1.
    Little PJ, Jennings GL, Skews H, Bobik A (1982) Bioavailability of dihydroergotamine in man. Br J Clin Pharmacol 13: 785–790Google Scholar
  2. 2.
    Aellig WH, Nüesch E (1977) Comparative pharmacokinetic investigations with tritium labeled ergot alkaloids after oral and intravenous administration in man. Int J Clin Pharmacol 15: 106–112Google Scholar
  3. 3.
    Bobik A, Jennings G, Skews H, Esler M, McLeane A (1981) Low oral bioavailability of dihydroergotamine and first pass extraction in patients with orthostatic hypotension. Clin Pharmacol Ther 30: 673–79Google Scholar
  4. 4.
    Müller E (1984) Pharmacological actions of the main metabolites of dihydroergotamine. Eur J Clin Pharmacol (in press)Google Scholar
  5. 5.
    Aellig W (1984) Investigation on the venoconstrictor effect of 8′-hydroxy-dihydroergotamine — the main metabolite of dihydroergotamine — in man. Eur J Clin Pharmacol 26: 239–242Google Scholar
  6. 6.
    Meier J, Schreier E (1976) Human plasma levels of some antimigraine drugs. Headache 16: 96–104Google Scholar
  7. 7.
    Matsubara T, Koike M, Touchi A, Tochino Y, Sugeno K (1976) Quantitative determination of cytochrome P-450 in rat liver homogenate. Anal Biochem 75: 596–603Google Scholar
  8. 8.
    Peroutka SJ, Snyder SH (1979) Multiple serotonin receptors: differential binding of [3H]5-hydroxyptamine, [3H]lysergic acid diethylamide and [3H]spiroperidol. Mol Pharmacol 16: 687–699Google Scholar
  9. 9.
    U'Prichard DC, Greenberg DA, Snyder SH (1977) Binding characteristics of a radiolabelled agonist and antagonist at central nervous system alpha noradrenergic receptors. Mol Pharmacol 13: 454–473Google Scholar
  10. 10.
    Burt DR, Creese I, Snyder SH (1976) Properties of [3H]haloperidol and [3H]dopamine binding associated with dopamine receptors of calf-brain membranes. Mol Pharmacol 12: 800–812Google Scholar
  11. 11.
    Creese I, Schneider R, Snyder SH (1977) [3H]spiroperidol labels dopamine receptors in pituitary and brain. Eur J Pharmacol 46: 377–381Google Scholar
  12. 12.
    Closse A, Frick W, Hauser D, Sauter A (1980) Characterization of [3H]-bromocriptine binding to calf caudate membranes, in psychopharmacology and biochemistry of neurotransmitter receptors. Dev Neurosci 11: 463–474Google Scholar
  13. 13.
    Maurer G (1977) Isolement et structure de métabolites biliaires de la dihydroergokryptine chez le rat. Thèse de docteur d'état es-sciences présentée devant l'Institut National des Sciences Appliquées de Lyon et l'Université Claude Bernard Lyon I. No d'ordre IDE 77014Google Scholar
  14. 14.
    Maurer G, Schreier E, Delaborde S, Loosli HR, Nufer R, Shukla AP (1982) Fate and disposition of bromocriptine in animals and man. I: Structure elucidation of the metabolites. Eur J Drug Metab Pharmacokinet 7: 281–292Google Scholar
  15. 15.
    Closse A, Bolliger G, Dravid A, Frick W, Hauser D, Pfäffli P, Sauter A, Tobler HJ (1983) Structural modifications of the ergopeptine molecule and their differential influence on the affinities to different receptor binding sites. A structure affinity analysis. In: Segawa T et al. (eds) Molecular pharmacology of neurotransmitter receptors. ed Raven Press, New York, pp 269–279Google Scholar
  16. 16.
    Maurer G, Schreier E, Delaborde S, Nufer R, Shukla AP (1983) Fate and disposition of bromocriptine in animals and man. II: Absorption, elimination and metabolism. Eur J Drug Metab Pharmacokinet 8: 51–62Google Scholar
  17. 17.
    Nimmerfall F, Rosenthaler J (1976) Ergot alkaloids: hepatic distribution and estimation of absorption by measurement of total radioactivity in bile and urine. J Pharmacokinet Biopharm 4: 57–66Google Scholar

Copyright information

© Springer-Verlag 1984

Authors and Affiliations

  • G. Maurer
    • 1
  • W. Frick
    • 1
  1. 1.Pharmaceutical Research and Development and Preclinical ResearchSandoz Ltd.BasleSwitzerland

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