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Psychopharmacology (Berl). 1988;94(3):386-91. doi: 10.1007/BF00174694.

Kinetics, brain uptake, and receptor binding characteristics of flurazepam and its metabolites.

Psychopharmacology

L G Miller, D J Greenblatt, D R Abernethy, H Friedman, M D Luu, S M Paul, R I Shader

Affiliations

  1. Division of Clinical Pharmacology, Tufts University School of Medicine, Boston, MA 02111.

PMID: 2833762 DOI: 10.1007/BF00174694

Abstract

The benzodiazepine derivative flurazepam (FLZ) is widely used as a hypnotic, but the relative contributions of FLZ and its metabolites desalkylflurazepam (DA-FLZ), hydroxyethylflurazepam (ETOH-FLZ), and flurazepam aldehyde (CHO-FLZ) to overall clinical activity remain uncertain. A single 20 mg/kg dose of FLZ.HCl was administered to mice, with plasma and brain concentrations of FLZ and metabolites determined during 5 h after dosage. Brain and plasma concentrations of FLZ were maximal at 0.5 h after dosage, then declined rapidly in parallel, whereas those of DAFLZ were maximal at 2 h, then declined slowly. Concentrations of ETOH-FLZ, the most polar metabolite, were maximal at 0.5 h, and were undetectable after 3 h. Little CHO-FLZ was detected in either brain or plasma. A single 30-mg oral dose of FLZ.HCl was given to 18 human volunteers, with plasma levels determined over 9 days. FLZ was detected in plasma at low concentrations for no more than 3 h after dosage. ETOH-FLZ concentrations were higher and persisted for 8 h after dosage. CHO-FLZ reached intermediate peak levels and was present longer than FLZ or ETOH-FLZ. In contrast, DA-FLZ achieved the greatest peak concentrations, occurring at 10 h after dosage. Levels declined very slowly, with a mean half-life of 71.4 h, and were still detectable 9 days after FLZ dosage. Plasma free fractions (percent unbound) in mice were 40.3, 51.4, and 25.0% for FLZ, ETOH-FLZ and DA-FLZ, respectively; in humans, values were 17.2, 35.2, and 3.5%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

References

  1. Br J Anaesth. 1983 Oct;55(10):985-9 - PubMed
  2. J Clin Pharmacol. 1982 May-Jun;22(5-6):259-63 - PubMed
  3. Neuropharmacology. 1985 Aug;24(8):751-9 - PubMed
  4. J Pharmacol Exp Ther. 1987 Feb;240(2):516-22 - PubMed
  5. J Pharm Pharmacol. 1984 Jun;36(6):400-1 - PubMed
  6. Age Ageing. 1984 Nov;13(6):335-43 - PubMed
  7. Psychopharmacology (Berl). 1984;82(4):395-9 - PubMed
  8. Life Sci. 1986 Jul 14;39(2):161-8 - PubMed
  9. J Clin Psychopharmacol. 1983 Apr;3(2):129-32 - PubMed
  10. Arzneimittelforschung. 1987 Jan;37(1):2-6 - PubMed
  11. Drug Metab Dispos. 1985 Jan-Feb;13(1):1-4 - PubMed
  12. Biopharm Drug Dispos. 1984 Apr-Jun;5(2):127-39 - PubMed
  13. Psychopharmacology (Berl). 1986;88(3):267-70 - PubMed
  14. Chem Pharm Bull (Tokyo). 1975 Aug;23(8):1826-33 - PubMed
  15. Ann Intern Med. 1975 Aug;83(2):237-41 - PubMed
  16. Anal Chem. 1981 May;53(6):793-7 - PubMed
  17. Br J Psychiatry. 1978 Sep;133:249-60 - PubMed
  18. J Pharmacol Exp Ther. 1983 Oct;227(1):98-106 - PubMed
  19. Psychopharmacology (Berl). 1987;93(1):72-6 - PubMed
  20. J Clin Pharmacol. 1985 Nov-Dec;25(8):613-5 - PubMed
  21. J Pharm Pharmacol. 1983 Mar;35(3):179-80 - PubMed
  22. Arzneimittelforschung. 1980;30(11):1944-7 - PubMed
  23. J Biol Chem. 1951 Nov;193(1):265-75 - PubMed
  24. Am J Psychiatry. 1984 Feb;141(2):191-5 - PubMed
  25. J Anal Toxicol. 1988 May-Jun;12(3):122-5 - PubMed
  26. N Engl J Med. 1975 Oct 2;293(14):702-5 - PubMed
  27. Clin Pharmacol Ther. 1975 Jan;17(1):1-14 - PubMed
  28. Clin Pharmacol Ther. 1981 Oct;30(4):475-86 - PubMed
  29. Drug Metab Dispos. 1983 Jan-Feb;11(1):70-2 - PubMed

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