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OtherDRUG METABOLISM AND DISPOSITION

Metabolite Involvement in Bromocriptine-Induced Prolactin Inhibition in Rats

Delphine Valente, Marcel Delaforge, Saik Urien, Dominique Guivarc’H, Raymond Vienet, Jean-Marc Grognet and Eric Ezan
Journal of Pharmacology and Experimental Therapeutics September 1997, 282 (3) 1418-1424;
Delphine Valente
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Marcel Delaforge
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Saik Urien
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Dominique Guivarc’H
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Raymond Vienet
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Jean-Marc Grognet
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Eric Ezan
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Abstract

Bromocriptine (BCT) is a dopamine D2 receptor agonist used for the treatment of Parkinson’s disease and hyperprolactinemic disorders. After oral administration, BCT is metabolized into mono- or dihydroxylated metabolites. To study how these metabolites influence parent drug pharmacodynamics, we administered BCT to rats intravenously (1 mg/kg i.v.) and orally (10 mg/kg p.o.) and measured the inhibition of prolactin secretion. Despite similar areas under the curve for BCT, the duration of the effect was 36 h after oral and only 18 h after intravenous administration. Pharmacokinetic/pharmacodynamic models were used to correlate the concentration of BCT in the effect compartment with the lowering of prolactin. One of these models (effect compartment model) showed that the effective concentration (EC50) at the site of action was much lower after oral (0.56 nM) than after intravenous administration (3.68 nM). In contrast, the EC50 values based on BCT metabolite data were in the same range for both administrations. These observations suggested the activity of one or more BCT metabolites. To confirm this hypothesis, hydroxylated metabolites of BCT (producedin vitro by rat liver microsomes) were administered i.v. (100 μg/kg) in rats. We found that monohydroxylated BCT was able to lower prolactin secretion like BCT. Dihydroxylated metabolites, as well as monohydroxylated metabolites, were effective in reducing in vitro prolactin secretion. Because we demonstrated that the concentration of hydroxylated metabolites after oral administration is 55-fold that of BCT, it can be concluded that BCT activity in the pituitary after oral administration is mediated by its metabolites.

Footnotes

  • Send reprint requests to: Ezan Eric, CEA, Service de Pharmacologie et d’Immunologie, Saclay, 91191 Gif-sur-Yvette Cedex, France.

  • Abbreviations:
    BCT
    bromocriptine
    i.v.
    intravenous
    p.o.
    per os
    EC50
    equivalent concentration for 50% of the maximum effect
    I.D. internal diameter
    O.D. overall diameter
    V
    volume
    Cmax
    maximal concentration
    Tmax
    time for theC max
    Cp
    concnetration in the central compartment
    Ce
    concentration in the effect compartment
    n
    Hill factor, AUC, area under the curve
    K1e
    rate of drug transfer between plasma and the effect site
    Keo
    rate of elimination from the effect site
    E
    effect
    Emax
    maximum effect
    Kin and kout
    rate of prolactin input and output from the central compartment, respectively
    PRL
    prolactin
    NADPH
    nicotinamide adenine dinucleotide phosphate, reduced form
    NADP
    nicotinamide adenine dinucleotide phosphate
    HPLC
    high-performance liquid chromatography
    • Received September 19, 1996.
    • Accepted May 2, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 282, Issue 3
1 Sep 1997
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OtherDRUG METABOLISM AND DISPOSITION

Metabolite Involvement in Bromocriptine-Induced Prolactin Inhibition in Rats

Delphine Valente, Marcel Delaforge, Saik Urien, Dominique Guivarc’H, Raymond Vienet, Jean-Marc Grognet and Eric Ezan
Journal of Pharmacology and Experimental Therapeutics September 1, 1997, 282 (3) 1418-1424;

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OtherDRUG METABOLISM AND DISPOSITION

Metabolite Involvement in Bromocriptine-Induced Prolactin Inhibition in Rats

Delphine Valente, Marcel Delaforge, Saik Urien, Dominique Guivarc’H, Raymond Vienet, Jean-Marc Grognet and Eric Ezan
Journal of Pharmacology and Experimental Therapeutics September 1, 1997, 282 (3) 1418-1424;
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