European Journal of Clinical Pharmacology

, Volume 21, Issue 2, pp 161–163 | Cite as

Clearance of diazepam can be impaired by its major metabolite desmethyldiazepam

  • U. Klotz
  • I. Reimann
Short Communication


The pharmacokinetics of a single intravenous dose of diazepam 0.1 mg/kg was studied in 6 healthy volunteers, in random order under controlled conditions and following pretreatment with its major metabolite, desmethyldiazepam (20 mg/day) for one week. In the two subjects with the highest plasma concentration of desmethyldiazepam (990 and 1100 ng/ml, respectively), total plasma clearance (Cl) of diazepam was reduced after desmethyldiazepam, by 31% and 54%, respectively. In three individuals there was a moderate decrease of 14% to 21%, and no effect was seen in one volunteer. Cl was significantly reduced (11.5±1.8 vs. 9.1±3.3 ml/min;p=0.015) and elimination half-life tended to be prolonged (38.5±10.4 vs. 65.8±67.1 h;p=0.15). It is concluded that high concentrations of desmethyldiazepam can influence the elimination of its parent drug diazepam by product inhibition.

Key words

diazepam desmethyldiazepam product inhibition pharmacokinetics 


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  1. 1.
    Schwartz MA, Koechlin BA, Postma E, Palmer S, Krol G (1965) Metabolism of diazepam in rat, dog and man. J Pharmacol Exp Ther 149: 423–435Google Scholar
  2. 2.
    Klotz U, Antonin KH, Bieck PR (1976) Comparison of the pharmacokinetics of diazepam after single and subchronic doses. Eur J Clin Pharmacol 10: 121–126Google Scholar
  3. 3.
    Rutherford DM, Okoko A, Tyrer PJ (1978) Plasma concentrations of diazepam and desmethyldiazepam during chronic diazepam therapy. Br J Clin Pharmacol 6: 69–73Google Scholar
  4. 4.
    Greenblatt DJ, Laughren TP, Allen MD, Harmatz JS, Shader RI (1981) Plasma diazepam and desmethyldiazepam concentrations during long-term diazepam therapy. Br J Clin Pharmacol 1: 35–40Google Scholar
  5. 5.
    van der Kleijn E, van Rossum JM, Muskens ETJM, Rijntjes NVM (1971) Pharmacokinetics of diazepam in dogs, mice and humans. Acta Pharmacol Toxicol 29 (Suppl 3): 109–127Google Scholar
  6. 6.
    Kaplan SA, Jack ML, Alexander K, Weinfield RE (1973) Pharmacokinetic profile of diazepam following single intravenous and oral and chronic oral administration. J Pharm Sci 62: 1789–1796Google Scholar
  7. 7.
    Klotz U, Avant GR, Hoyumpa A, Schenker S, Wilkinson GR (1975) The effects of age and liver disease on the disposition and elimination of diazepam in adult man. J Clin Invest 55: 347–359Google Scholar
  8. 8.
    Klotz U, Antonin KH, Bieck PR (1976) Pharmacokinetics and plasma binding of diazepam in man, dog, rabbit, guinea pig and rat. J Pharmacol Exp Ther 199: 67–73Google Scholar
  9. 9.
    Eatman FB, Colburn WA, Boxenbaum HG, Posmanter HN, Weinfield RE, Ronfeld R, Weissmann L, Moore JD, Gibaldi M, Kaplan SA (1977) Pharmacokinetics of diazepam following multiple-dose oral administration to healthy human subjects. J Pharmacokinet Biopharm 5: 481–494Google Scholar
  10. 10.
    Berman M, Weiss MF (1974) SAAM Manual, Laboratory of Theoretical Biology, National Institute of Health, Bethesda MarylandGoogle Scholar
  11. 11.
    Riegelman S, Loo JCK, Rowland M (1968) Shortcomings in pharmacokinetic analysis by conceiving the body to exhibit the properties of a single compartment. J Pharm Sci 57: 117–123Google Scholar
  12. 12.
    Jusko WJ, Gibaldi M (1972) Effects of change in elimination on various parameters of the two-compartment open model. J Pharm Sci 61: 1270–1273Google Scholar
  13. 13.
    von Bahr C (1970) Binding to cytochrome P-450 and metabolism of desmethylimipramine and metabolites in rat liver microsomes. Acta Pharmacol Toxicol 28 (Suppl 1): 13Google Scholar
  14. 14.
    Jähnchen E, Levy G (1972) Inhibition of phenylbutazone elimination by its metabolite oxyphenbutazone. Proc Soc Exp Biol Med 141: 963–965Google Scholar
  15. 15.
    Soda DM, Levy G (1975) Inhibition of drug metabolism by hydroxylated metabolites: Cross-inhibition and specificity. J Pharm Sci 64: 1928–1931Google Scholar
  16. 16.
    Bast A, Noordhoek J (1981) Product inhibition during hepatic microsomal N-demethylation of aminopyrine in the rat. Biochem Pharmacol 30: 19–24Google Scholar

Copyright information

© Springer-Verlag 1981

Authors and Affiliations

  • U. Klotz
    • 1
  • I. Reimann
    • 1
  1. 1.Dr. Margarete Fischer Bosch Institut für Klinische PharmakologieStuttgartGermany

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