The pharmacokinetics and biotransformation of14C-Lisuride hydrogen maleate in rhesus monkey and in man
- 10 Downloads
14C-labelled lisuride hydrogen maleate was administered intravenously (25 ug) and orally (200 ug) to three male and three female elderly volunteers. Following i.v. injection radioimmunologically determined plasma levels of unchanged lisuride showed a three-phasic decline with half-lives of 3 minutes, 16 minutes and 2.9 hours. The total clearance was 16 ± 9 ml/min/kg. Bioavailability was estimated to be 14% of oral dose.
Determination of 1 4C-radioactivity did not show any specific enrichment of lisuride metabolites in cellular components of blood. The drug was almost totally metabolized and its degradation products were eliminated equally via the kidney and liver. Total recovery was about 90% of dose. The elimination half-life was 10 hours. Small parts of the dose administered were renally excreted with a halflife of 23 hours. Lisuride is metabolized extensively. HPLC radiochromatograms of freely extractable metabolites from urine did not show marked differences between both routes of administration. More than 15 compounds were freely extractable, only one of them represented more than 5% of dose. Phase II reactions were quantitatively unimportant.
From rhesus monkey urine 6 metabolites were isolated. Chemical structures were proposed for 5 of them. They were assigned to the pattern of freely extractable human urinary metabolites and covered about 50% of radiolabel corresponding to about 13% of dose.
The main freely extractable urinary metabolite was thought to be the 2-keto-3-hydroxy-lisuride derivative. Structures of the other four metabolites and earlier observations on the stability of the N′-ethyl-3H label led to the interpretation of independent changes of lisuride by different enzymatic processes such as oxidative N-deethylation, hydroxylation of the benzene system, monooxygenation at C2 and C9, and oxidation of double bonds atC2/C3 and C9/Ci0.
Key wordsLisuride ergolines metabolism pharmacokinetics monkey man
Unable to display preview. Download preview PDF.
- 2.Wachtel H. (1983): Central dopaminergic, and antidopaminergic effects of ergot derivatives structurally related to lisuride. In Calne D.B. et al. (EDTS): Lisuride and Other Dopamine Agonists, Raven Press, New-York (1983), 109–125.Google Scholar
- 3.Schneider W.H.F. (1983): Lisuride and female fertility. In Calne D.B. et al. (EDTS): Lisuride and Other Dopamine Agonists, Raven Press, New-York (1983), 331–335.Google Scholar
- 4.Schmidt-Gollwitzer M. (1983): Suppression of Lactation. In Calne D.B. et al. (EDTS): Lisuride and Other Dopamine Agonists, Raven Press, New-York, 301–312.Google Scholar
- 5.Liuzzi A., Chiodini P.G., Oppizzi G., Dallabonzana D., Spelta B., Silvestini F., Rainer E. and Horowski R. (1983): Medical treatment of pituitary adénomes: Effects on hormonal secretion and tumor size. In Calne D.B. et al. (EDTS): Lisuride and Other Dopamine Agonists, Raven Press, New-York, 231–238.Google Scholar
- 6.Liebermann A.N., Goldstein M., Gopinathan G., Neophytides A., Leibowitz M., Walker R. and Hiesinger E. (1983): Lisuride in Parkinson’s disease and related disorders. In Calne D.B. et al. (EDTS): Lisuride and Other Dopamine Agonists, Raven Press, New-York, 419–429.Google Scholar
- 8.Toda T. and Oshino N. (1980): Biotransformation of lisuride in the hemoglobin-free perfused rat liver and the whole animal. Drug. Metab. Dispos.,9, 108–113.Google Scholar
- 11.Documenta Geigy (1975): 7th Edition, p. 552.Google Scholar
- 12.Giebler A., Poland H. and Woloszczak R.: A program library for computing the parameters of linear compartment models in pharmacokinetics. Proceedings of the 4th International Congress of Cybernetics and Systems, Amsterdam (1978). In: Rose J.: Current Topics in Cybernetics and Systems, Berlin, Heidelberg, New-York, Springer Verlag.Google Scholar
- 14.Aellig W.H. and Nüesch E. (1977): Comparative pharmacokinetic investigations with tritium-labelled ergot alkaloids after oral and intravenous administration tö man. Int. J. Clin. Pharmacol., 15, 106–112.Google Scholar
- 15.Unpublished own results (from 1974).Google Scholar