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. 1986 Oct;22(4):421–428. doi: 10.1111/j.1365-2125.1986.tb02912.x

Pharmacokinetics of the new benzodiazepine antagonist Ro 15-1788 in man following intravenous and oral administration.

G Roncari, W H Ziegler, T W Guentert
PMCID: PMC1401170  PMID: 3094572

Abstract

During clinical pharmacology studies with the benzodiazepine antagonist Ro 15-1788 the pharmacokinetic characteristics of high intravenous doses (20 and 40 mg) and of an oral dose (200 mg) were examined in six healthy male volunteers. Ro 15-1788 was rapidly and extensively distributed in the body with an apparent volume of distribution Vss of 1.06 l kg-1. Elimination occurred rapidly by hepatic metabolism and the high plasma clearance of 1.14 l min-1 resulted in a short elimination half-life of less than 1 h. No difference in the disposition parameters calculated from the data after the 20 and 40 mg doses was observed reflecting a dose-proportionality in the areas under plasma concentration-time curves and unchanged distribution characteristics. Because the blood/plasma distribution coefficient is close to unity the disposition parameters obtained from plasma concentrations are similar to the corresponding parameters with reference to blood. Following oral administration of 200 mg the drug is rapidly absorbed. Peak levels were reached after 20-90 min and were close to or even higher than the values after the 40 mg intravenous dose at the same time point. Due to the high hepatic extraction ratio the fraction reaching the systemic circulation unchanged was reduced to approximately 16% during the absorption step.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Allonen H., Ziegler G., Klotz U. Midazolam kinetics. Clin Pharmacol Ther. 1981 Nov;30(5):653–661. doi: 10.1038/clpt.1981.217. [DOI] [PubMed] [Google Scholar]
  2. Amrein R., Cano J. P., Eckert M., Coassolo P. Pharmakokinetik von Midazolam nach intravenöser Verabreichung. Arzneimittelforschung. 1981;31(12A):2202–2205. [PubMed] [Google Scholar]
  3. Benet L. Z., Galeazzi R. L. Noncompartmental determination of the steady-state volume of distribution. J Pharm Sci. 1979 Aug;68(8):1071–1074. doi: 10.1002/jps.2600680845. [DOI] [PubMed] [Google Scholar]
  4. Darragh A., Lambe R., Kenny M., Brick I. Tolerance of healthy volunteers to intravenous administration of the benzodiazepine antagonist Ro 15-1788. Eur J Clin Pharmacol. 1983;24(4):569–570. doi: 10.1007/BF00609905. [DOI] [PubMed] [Google Scholar]
  5. Darragh A., Lambe R., O'Boyle C., Kenny M., Brick I. Absence of central effects in man of the benzodiazepine antagonist Ro 15-1788. Psychopharmacology (Berl) 1983;80(2):192–195. doi: 10.1007/BF00427969. [DOI] [PubMed] [Google Scholar]
  6. Darragh A., Lambe R., Scully M., Brick I., O'Boyle C., Downe W. W. Investigation in man of the efficacy of a benzodiazepine antagonist, Ro 15-1788. Lancet. 1981 Jul 4;2(8236):8–10. doi: 10.1016/s0140-6736(81)90251-8. [DOI] [PubMed] [Google Scholar]
  7. Eberts F. S., Jr, Philopoulos Y., Reineke L. M., Vliek R. W. Triazolam disposition. Clin Pharmacol Ther. 1981 Jan;29(1):81–93. doi: 10.1038/clpt.1981.14. [DOI] [PubMed] [Google Scholar]
  8. Gaillard J. M., Blois R. Effect of the benzodiazepine antagonist Ro 15-1788 on flunitrazepam-induced sleep changes. Br J Clin Pharmacol. 1983 May;15(5):529–536. doi: 10.1111/j.1365-2125.1983.tb02086.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Hunkeler W., Möhler H., Pieri L., Polc P., Bonetti E. P., Cumin R., Schaffner R., Haefely W. Selective antagonists of benzodiazepines. Nature. 1981 Apr 9;290(5806):514–516. doi: 10.1038/290514a0. [DOI] [PubMed] [Google Scholar]
  10. Klotz U., Duka T., Dorow R., Doenicke A. Flunitrazepam and lormetazepam do not affect the pharmacokinetics of the benzodiazepine antagonist Ro 15-1788. Br J Clin Pharmacol. 1985 Jan;19(1):95–98. doi: 10.1111/j.1365-2125.1985.tb02619.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Klotz U., Ziegler G., Reimann I. W. Pharmacokinetics of the selective benzodiazepine antagonist Ro 15-1788 in man. Eur J Clin Pharmacol. 1984;27(1):115–117. [PubMed] [Google Scholar]
  12. Lupolover Y., Safran A. B., Desangles D., de Weisse C., Meyer J. J., Bousquet A., Assimacopoulos A. Evaluation of visual function in healthy subjects after administration of Ro 15-1788. Eur J Clin Pharmacol. 1984;27(4):505–507. doi: 10.1007/BF00549604. [DOI] [PubMed] [Google Scholar]
  13. Möhler H., Richards J. G. Agonist and antagonist benzodiazepine receptor interaction in vitro. Nature. 1981 Dec 24;294(5843):763–765. doi: 10.1038/294763a0. [DOI] [PubMed] [Google Scholar]
  14. Rowland M. Influence of route of administration on drug availability. J Pharm Sci. 1972 Jan;61(1):70–74. doi: 10.1002/jps.2600610111. [DOI] [PubMed] [Google Scholar]
  15. Timm U., Zell M. Determination of the benzodiazepine antagonist Ro 15-1788 in plasma by high-performance liquid chromatography with UV detection. Arzneimittelforschung. 1983;33(3):358–362. [PubMed] [Google Scholar]

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