Advertisement

Psychopharmacology

, Volume 66, Issue 3, pp 267–274 | Cite as

Single- and multiple-dose kinetics of estazolam, a triazolo benzodiazepine

  • Marcia Divoll Allen
  • David J. Greenblatt
  • John D. Arnold
Original Investigations

Abstract

The pharmacokinetic properties of estazolam, a triazolo benzodiazepine hypnotic agent, were assessed in a series of healthy volunteers following single and multiple doses. After single oral doses of 2–16 mg, peak plasma concentrations were reached within 6 h. Values of elimination half-life ranged from 8.3–31.2 h (mean 17.0 h) and did not vary significantly with dose. During 3 weeks of therapy, steady-state plasma concentrations increased approximately in proportion to increasing doses, and accumulation was essentially complete within 3 days of each dose change. The mean observed accumulation ratio was 1.84, which was slightly larger than the predicted ratio of 1.53. Exposure to multiple-dose estazolam therapy had no significant influence on the kinetics of a single dose of antipyrine, suggesting that estazolam neither stimulates nor inhibits enzyme activity in humans. Thus the accumulation and elimination kinetics of estazolam can be classified as intermediate to those of the short-acting (such as oxazepam) and the long-acting (such as diazepam) benzodiazepine derivatives.

Key words

Benzodiazepines Estazolam Drug accumulation Pharmacokinetics 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Boxenbaum, H. G., Riegelman, S., Elashoff, R. M.: Statistiscal estimations in pharmacokinetics. J. Pharmacokinet. Biopharm. 2, 123–148 (1974)Google Scholar
  2. Brodie, B. B., Axelrod, J., Soberman, R., Levy, B. B.: The estimation of antipyrine in biological materials. J. Biol. Chem. 179, 25–29 (1949)Google Scholar
  3. de Silva, J. A. F., Puglisi, C. V.: Determination of medazepam (Nobrium), diazepam (Valium) and their major biotransformation products in blood and urine by electron capture gasliquid chromatography. Anal. Chem. 42, 1725–1736 (1970)Google Scholar
  4. Gibaldi, M., Perrier, D.: Pharmacokinetics. New York: Marcel Dekker 1975Google Scholar
  5. Greenblatt, D. J.: Determination of desmethyldiazepam in plasma by electron-capture GLC: Application to pharmacokinetic studies of clorazepate. J. Pharm. Sci. 67, 427–429 (1978a)Google Scholar
  6. Greenblatt, D. J.: Simultaneous gas chromatographic analysis of diazepam and its major metabolite desmethyldiazepam, with use of double internal standardization. Clin. Chem. 24, 1838–1841 (1978b)Google Scholar
  7. Greenblatt, D. J.: Predicting steady-state serum concentrations of drugs. Annu. Rev. Pharmacol. Toxicol. 19, 347–356 (1979)Google Scholar
  8. Greenblatt, D. J., Koch-Weser, J.: Clinical pharmacokinetics. New Engl. J. Med. 293, 702–705, 964–970 (1975)Google Scholar
  9. Greenblatt, D. J., Locniskar, A.: Spectrophotometric assay of antipyrine in plasma: a reevaluation. Int. J. Clin. Pharmacol. Biopharm. (in press, 1979)Google Scholar
  10. Greenblatt, D. J., Shader, R. I.: Benzodiazepines in clinical practice. New York: Raven 1974Google Scholar
  11. Greenblatt, D. J., Shader, R. I.: Pharmacokinetic understanding of antianxiety drug therapy. South. Med. J. 71 (Suppl. 2), 2–9 (1978)Google Scholar
  12. Greenblatt, D. J., Allen, M. D., MacLaughlin, D. S., Huffman, D. H., Harmatz, J. S., Shader, R. I.: Single- and multiple-dose kinetics of oral lorazepam in humans: The predictability of accumulation. J. Pharmacokinet. Biopharm. 7, 159–179 (1979a)Google Scholar
  13. Greenblatt, D. J., Franke, K., Shader, R. I.: Analysis of lorazepam and its glucuronide metabolite by electron-capture gas-liquid chromatography: Use in pharmacokinetic studies of lorazepam. J. Chromatogr. 146, 311–320 (1978)Google Scholar
  14. Greenblatt, D. J., Pfeifer, H. J., Ochs, H. R., Franke, K., MacLaughlin, D. S., Smith, T. W., Koch-Weser, J.: Pharmacokinetics of quinidine in humans after intravenous, intramuscular and oral administration. J. Pharmacol. Exp. Ther. 202, 365–378 (1977)Google Scholar
  15. Greenblatt, D. J., Shader, R. I., Franke, K., MacLaughlin, D. S., Harmatz, J. S., Allen, M. D., Werner, A., Woo, E.: Pharmacokinetics and bioavailability of intraveous, intramuscular and oral lorazepam in humans. J. Pharm. Sci. 68, 57–63 (1979b)Google Scholar
  16. Isozaki, H., Tanaka, M., Inanaga, K.: Effect of a triazolobenzodiazepine derivative, estazolam, on all-night sleep pattern. Curr. Ther. Res. 20, 493–509 (1976)Google Scholar
  17. Kanai, Y.: The biotransformation of 8-chloro-6-phenyl-4H-s-triazolo [4,3,-a] [1,4] benzodiazepine (D-40TA), a new central depressant, in man, dog and rat. Xenobiotica 4, 441–456 (1974)Google Scholar
  18. Loo, J. C. K., Riegelman, S.: Assessment of pharmacokinetic constants from postinfusion blood curves obtained after IV infusion. J. Pharm. Sci. 59, 53–55 (1970)Google Scholar
  19. Marquardt, D. W.: An algorithm for least-squares estimation of non-linear parameters. J. Soc. Ind. Appl. Math. 11, 431–441 (1963)Google Scholar
  20. Momose, T., Ishii, S., Kuge, T.: Controlled comparison of estazolam and nitrazepam as hypnotics on the preoperative night sleep. Curr. Ther. Res. 19, 277–291 (1976)Google Scholar
  21. Usanis, R. A.: NLIN-Nonlinear least-squares estimation of parameters. Library Services Series No. LSR-089-1. North Carolina: Triangle Universities Computation Center 1972Google Scholar
  22. Vesell, E. S., Passananti, G. T., Viau, J.-P., Epps, J. E., DiCarlo, F. J.: Effects of chronic prazepam administration on drug metabolism in man and rat. Pharmacology 7, 179–206 (1972)Google Scholar
  23. Wagner, J. G.: Fundamentals of clinical pharmacokinetics Illinois: Drug Intelligence 1975Google Scholar

Copyright information

© Springer-Verlag 1979

Authors and Affiliations

  • Marcia Divoll Allen
    • 1
  • David J. Greenblatt
    • 1
  • John D. Arnold
    • 2
  1. 1.Clinical Pharmacology UnitMassachusetts General HospitalBostonUSA
  2. 2.Quincy Research CenterKansas CityUSA

Personalised recommendations