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Single and multiple dose pharmacokinetics of etizolam in healthy subjects

Summary

The pharmacokinetics of etizolam, a new thienodiazepine derivative, has been examined after single and multiple (0.5 mg tablet) (0.5 mg b.d for 1 week) oral therapeutic doses in healthy volunteers. The single-dose kinetic profile of etizolam suggested that absorption after oral dosage was reasonably rapid, the maximum plasma concentration (Cmax) being attained within 0.5–2 h in all subjects. The mean elimination half-life (t1/2) averaged 3.4 h. Consistent with this, steady-state concentration were rapidly achieved and accumulation was extremely limited. Predicted average plasma concentrations (Cp) did not differ significantly from those actually measured at steady-state, suggesting that the kinetics of etizolam was linear, at least at therapeutic doses. The mean wash-out t1/2 was comparable to the elimination t1/2 of the single dose, which means that the drug probably has no effect on hepatic microsomal enzymes and other kinetic variables after repeated dosing. At steady state plasma concentrations of the main metabolite, α-hydroxyetizolam, were higher and disappeared more slowly (mean t1/2 8.2 h) than those of the parent compound. Taken with the fact that in animals the metabolite shows almost the same potency of pharmacological action as etizolam, this suggests that it may contribute significantly to the clinical effects of the parent compound. Based on the kinetic characteristics of the parent drug and its metabolite, etizolam can be regarded as a short-acting benzodiazepine, with elimination kinetics between those of short-intermediate derivatives and ultra-rapidly eliminated benzodiazepines.

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References

  1. 1.

    Tahara T, Araki K, Shiroki M, Matsuo H, Munakata T (1978) Syntheses and structure-activity relationships of 6-Aryl-4H-s-triazolo[3,4-c]thienol[2,3-e][1,4]diazepines. Arzneimittelforschung 28: 1153–1158

  2. 2.

    Nakanishi M, Tahara T, Araki K, Shiroki M, Tsumagari T, Takigawa Y (1973) Studies on psychotropic drugs. 18. Synthesis and structure-activity relationships of 5-phenyl-1,3-dihydro-2H-thieno[2,3-e][1,4]diazepin-2-ones. J Med Chem 16: 214–219

  3. 3.

    Tsumagari T, Nakajima A, Fukuda T, Shuto S, Kenjo T, Morimoto Y, Takigawa Y (1987) Pharmacological properties of 6-(0-Chlorophenyl)-8-ethyl-1-methyl-4H-s-triazolo[3,4-c]thieno[2,3-e][1,4]diazepine(Y-7131), a new anti-anxiety drug Arzneimittel-forschung 28: 1158–1164

  4. 4.

    Itil TM, Menon GN, Itil KZ (1982) Computer EEG drug data base in psychopharmacology and in drug development. Psychopharma Bull 18: 165–172

  5. 5.

    Fukumizu Y (1979) Clinical trial of etizolam. J New Remedi Clin 28: 428–430

  6. 6.

    Kato Y, Nishimine H (1978) Absorption, distribution and excretion of a new thienodiazepine derivative (Y-7131) in rats and mice. Arzneimittelforschung 28: 1170–1173

  7. 7.

    Sacchi Landriani G, Guardabasso V, Rocchetti M (1983) NL-FIT: A microcomputer program for non-linear fitting. Comput Programs Biomed 16: 35–42

  8. 8.

    Gibaldi M, Perrier D (1982) Pharmacokinetics, 2nd ed. Dekker New York

  9. 9.

    Benet LZ, Galeazzi RL (1979) Noncomportmentol determination of the steady-state volume of distribution. J Pharm Sci 68: 1071–1074

  10. 10.

    Gibaldi M, Boyes RN, Feldman S (1971) Influence of first-pass effect on availability of drugs on oral administration. J Pharma Sci 60: 1338–1340

  11. 11.

    Greenblatt DJ, Divoll M, Abernethy DR, Ochs HR, Shader RI (1983) Clinical pharmacokinetics of the newer benzodiazepines. Clin Pharmacokinet 8: 233–252

  12. 12.

    Jochemsen R, Breimer DD (1984) Pharmacokinetics of benzodiazepines: Metabolic pathways and plasma level profiles. Curr med Res Opin (Suppl) 4: 60–78

  13. 13.

    Ochs HR, Greenblatt DJ, Verburg-Ochs B, Harmatz JS, Grehl H (1984) Disposition of clotiazepam: Influence of age, sex, oral contraceptives, cimetidine, isoniazid and ethanol. Eur J Clin Pharmacol 26: 55–59

  14. 14.

    Jochemsen R, Wesselman JGJ, Hermans J, van Boxtel CJ, Breimer DD (1983) Pharmacokinetics of brotizolam in healthy subjects following intravenous and oral administration. Br J Clin Pharmacol 16: 285S-290S

  15. 15.

    Jochemsen R, Wesselman JGJ, van Boxtel CJ, Hermans J, Breimer DD (1983) Comparative pharmacokinetics of brotizolam and triazolam in healthy subjects. Br J Clin Pharmacol 16: 291S-297S

  16. 16.

    Bechtel WD (1983) Pharmacokinetics and metabolism of brotizolam in humans. Br J Clin Pharmacol 16: 279S-283S

  17. 17.

    Arendt R, Ochs HR, Greenblatt DJ (1982) Electron capture GLC analysis of the thienodiazepine clotiazepam. Preliminary pharmacokinetic studies. Arzneimittelforschung 32: 453–455

  18. 18.

    Caccia S, Garattini S (1990) Formation of active metabolites of psychotropics: An updated review of their significance. Clin Pharmacokinet 18: 434–459

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Fracasso, C., Confalonieri, S., Garattini, S. et al. Single and multiple dose pharmacokinetics of etizolam in healthy subjects. Eur J Clin Pharmacol 40, 181–185 (1991). https://doi.org/10.1007/BF00280074

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Key words

  • Etizolam
  • α-hydroxyetizolam
  • healthy subjects
  • kinetics