Advertisement

Pharmacokinetics of flutoprazepam, a novel benzodiazepine drug, in normal subjects

  • N. Barzaghi
  • L. Leone
  • M. Monteleone
  • G. Tomasini
  • E. Perucca
Original Papers

Summary

The single dose pharmacokinetics of flutoprazepam and its active N-desalkyl metabolite were determined in 8 normal subjects by using newly developed, highly sensitive, GC-MS and HPLC techniques. Following a 2 mg dose of the drug, the concentrations of unchanged flutoprazepam in serum were extremely low (below 5 ng/ml at 2 h) and declined rapidly to undetectable levels within 6–9 h after dosing. At all sampling times, the serum concentration of the N-dealkylated metabolite (N-desalkylflurazepam) was much greater than that of the parent compound. This metabolite appeared in serum rapidly (within 2 h), reached a peak between 2 and 12 h and declined slowly, with an elimination half-life of about 90 h on average. The serum concentration of two additional putative metabolites (3-hydroxy-flutoprazepam and N-desalkyl-3-hydroxy-flutoprazepam) was below the limit of detection (2 ng/ml) in all samples. Mild CNS effects (documented by prolonged choice reaction time) were present at 2 and 4 h but were no longer detectable at 9 h. It is suggested that unchanged flutoprazepam is unlikely to contribute significantly to clinical effects and that the drug exerts its therapeutic activity through conversion to the slowly eliminated N-desalkyl metabolite.

Keywords

Flutoprazepam pharmacokinetics benzodiazepine humans 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Ueki S., Sukamoto T., Watanabe S.,et al. (1982): Behavioural effects of flutoprazepam (KB S09) and its metabolites. Pholia Pharmacol. Jpn., 80, 15–30.CrossRefGoogle Scholar
  2. 2.
    Kanebo Pharmaceuticals Ltd., unpublished data.Google Scholar
  3. 3.
    Tsutsui S., Nisbida K., Namba T., Saito T. (1982): Clinical study of KB 509 (flutoprazepam) on psychosomatic disorders and neuroses (double-blind test). Jpn. Pharmacol. Ther., 10, 6337–6351.Google Scholar
  4. 4.
    Kudo Y.,TanakaS. (1980): Clinical pharmacology of KB 509. In: Turner P., Padgham C. (eds), Abstracts World Conference on Clinical Pharmacology and Therapeutics, London, Abstract 0242.Google Scholar
  5. 5.
    Midorikawa T., Miura S., Sato M., Sakurai S., Awata N. (1982): The metabolic fate of 7-cbloro-l-cyclopropyl-methyll, 3-dihydro-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one (KB 509). I. Metabolism in dogs, mice and rats. Iyakukin. Kenkyu, 13, 309.Google Scholar
  6. 6.
    Sakurai S., Miura S., Sato M., Midorikawa T., Awata N. (1982): The metabolic fete of 7-chloro-l-cyclopropyl-methyl-1,3-dfliydro-5-(2-fluorophenyl)-2H-1,4-enzodiazepin-2-one (KB 509). II. Absorption, distribution and excretion in rats, mice and dogs. Iyakukin. Kenkyu, 13, 309.Google Scholar
  7. 7.
    Kageyama T. Phase I study of flutoprazepam (KB 509). Single dose study 1987. Kanebo Pharmaceuticals Ltd., Unpublished dataGoogle Scholar
  8. 8.
    Hindmarch I. (1980): Psychomotor function and psychoactive drugs. Br. J. Clin. Pharmacol., 10, 189–209.PubMedGoogle Scholar
  9. 9.
    Brodie R.R., Chassaud D.F., Taylor T. (1981): Concentrations of N-descyclopropylmethylprazepam in whole blood, plasma and milk after administration of prazepam to humans. Biopharm. Drug Dispos., 2, 59–68.CrossRefPubMedGoogle Scholar
  10. 10.
    Greenblatt D.J., Divoll M., Harmatz J., MacLaughlin D.S., Shatter Ri. (1981): Kinetics and clinical effects of flurazepam in young and elderly noninsomniacs. Clin. Pharmacol. Ther., 30, 475–486.PubMedGoogle Scholar
  11. 11.
    Greenblatt D.J., Shader R.I., Abemethy D.R. (1983): Current status of benzodiazepines. New Engl. J. Med., 309, 354–358.CrossRefPubMedGoogle Scholar
  12. 12.
    Schwartz M.A., Postma E. (1970): Metabolism of flurazepam, a benzodiazepine, in man and dog. J. Pharm. Sei., 59, 1800–1806.CrossRefGoogle Scholar
  13. 13.
    Kaplan S.A., de Silva J.A.F., Jack M.X., et al. (1973): Blood level profile in man following chronic oral administration of flurazepam hydrochloride. J. Pharm. Sei, 62, 1932–1935.CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 1989

Authors and Affiliations

  • N. Barzaghi
    • 3
  • L. Leone
    • 1
  • M. Monteleone
    • 1
  • G. Tomasini
    • 2
  • E. Perucca
    • 3
  1. 1.Regina Margherita HospitalTorinoItaly
  2. 2.Istituto De Angeli S.p.A.MilanoItaly
  3. 3.Department of Medical PharmacologyUniversity of PaviaPaviaItaly

Personalised recommendations