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
Originals

Summary

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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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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