Clinical Pharmacokinetics

, Volume 6, Issue 2, pp 89–105 | Cite as

Clinical Pharmacokinetics of Oxazepam and Lorazepam

  • David J. Greenblatt


Oxazepam and lorazepam are 3-hydroxy benzodiazepine derivatives used as sedatives and anxiolytics. The major metabolic pathway for both compounds involves conjugation to glucuronic acid at the 3-position, followed by urinary excretion of the inactive glucuronide metabolite.

Oxazepam has been administered to humans by the oral route only. Usual ranges for kinetic parameters are: elimination half-life, 5 to 15 hours; volume of distribution, 0.6 to 2.0L/kg; clearance, 0.9 to 2.0ml/min/kg. Age and liver disease have a minimal influence on oxazepam kinetics, but renal disease is associated with a prolonged half-life and increased volume of distribution.

Typical kinetic values for lorazepam are: elimination half-life, 8 to 25 hours; volume of distribution, 1.0 to 1.3L/kg; clearance, 0.7 to 1.2ml/min/kg. Lorazepam clearance is somewhat reduced in old age, but liver disease has a minimal effect on clearance. Oral and intramuscular lorazepam are rapidly absorbed, with systemic availability averaging 90 % or more.

Both oxazepam and lorazepam are extensively bound to plasma protein, but the free fraction for lorazepam (8 to 12%) is greater than that for oxazepam (2 to 4%).


Cimetidine Clinical Pharmacokinetic Oxazepam Disulfiram Acute Viral Hepatitis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Aaltonen, L.; Kanto, J. and Salo, M.: Cerebrospinal fluid concentrations and serum protein binding of lorazepam and its conjugate. Acta Pharmacologica et Toxicologics 46: 156–158 (1980).CrossRefGoogle Scholar
  2. Allen, M.D.; Greenblatt, D.J.; LaCasse, Y. and Shader, R.I.: Pharmacokinetic study of lorazepam overdosage. American Journal of Psychiatry 137: 1414–1415 (1980).PubMedGoogle Scholar
  3. Alvan, G.; Siwers, B. and Vessman, J.: Pharmacokinetics of oxazepam in healthy volunteers. Acta Pharmacologica et Toxicologica 40 (Suppl. 1): 40–51 (1977).PubMedGoogle Scholar
  4. Bliding, A.: Effects of different rates of absorption of two benzodiazepines on subjective and objective parameters. European Journal of Clinical Pharmacology 7: 201–211 (1974).PubMedCrossRefGoogle Scholar
  5. de Groot, G.; Maes, R.A.A.; Defoort, P. and Thiery, M.: Placental transfer of lorazepam. 1CRS Medical Science 3: 594 (1975).Google Scholar
  6. de Groot, G.; Maes, R.A.A. and Lemmens, H.H.J.: Determination of lorazepam in plasma by electron capture GLC. Archives of Toxicology 35: 229–234 (1976).PubMedCrossRefGoogle Scholar
  7. de Silva, J.A.F.; Bekersky, I.; Puglisi, C.V.; Brooks, M.A. and Weinfeld, R.E.: Determination of 1,4-benzodiazepines and diazepin-2-ones in blood by electron-capture gas-liquid chromatography. Analytical Chemistry 48: 10–19 (1976).PubMedCrossRefGoogle Scholar
  8. Desmond, P.V.; Patwardhan, R.; Schenker, S. and Speeg, K.V.: Cimetidine impairs the elimination of chlordiazepoxide (Librium) in humans. Annals of Internal Medicine 93: 266–268 (1980a).PubMedGoogle Scholar
  9. Desmond, P.V.; Roberts, R.K.; Wood, A.J.J.; Dunn, G.D.; Wilkinson, G.R. and Schenker, S.: Effect of heparin administration on plasma binding of benzodiazepines. British Journal of Clinical Pharmacology 9: 171–175 (1980b).PubMedCrossRefGoogle Scholar
  10. Dundee, J.W.; Lilburn, J.K.; Toner, W. and Howard, P.J.: Plasma lorazepam levels. A study following single dose administration of 2 and 4mg by different routes. Anaesthesia 33: 15–19 (1978).PubMedCrossRefGoogle Scholar
  11. Elliott, H.W.: Metabolism of lorazepam. British Journal of Anaesthesia 48: 1017–1023 (1976).PubMedCrossRefGoogle Scholar
  12. Forgione, A.; Martelli, P.; Marcucci, F.; Fanelli, R.; Mussini, E. and Jommi, G.C.: Gas-liquid chromatography and mass spectrometry of various benzodiazepines. Journal of Chromatography 59: 163–168 (1971).PubMedCrossRefGoogle Scholar
  13. Frigerio, A.; Baker, K.M. and Belvedere, G.: Gas Chromatographic degradation of several drugs and their metabolites. Analytical Chemistry 45: 1846–1851 (1973).PubMedCrossRefGoogle Scholar
  14. Giles, H.G.; Fan, T.; Naranjo, C.A. and Sellers, E.M.: A simple electron-capture gas Chromatographie analysis of oxazepam in plasma by determination of its thermal degradation production. Canadian Journal of Pharmaceutical Sciences 13: 64–66 (1978).Google Scholar
  15. Greenblatt, D.J. and Koch-Weser, J.: Intramuscular injection of drugs. New England Journal of Medicine 295: 542–546 (1976).PubMedCrossRefGoogle Scholar
  16. Greenblatt, D.J.; Shader, R.I. and Koch-Weser, J.: Pharmacokinetics in clinical medicine: Oxazepam versus other benzodiazepines. Diseases of the Nervous System 36 (No. 5, Sect. 2): 6–13 (1975).PubMedGoogle Scholar
  17. Greenblatt, D.J.; Schillings, R.T.; Kyriakopoulos, A.A.; Shader, R.I.; Sisenwine, S.F.; Knowles, J.A. and Ruelius, H.W.; Clinical pharmacokinetics of lorazepam. I. Absorption and disposition of oral 14C-lorazepam. Clinical Pharmacology and Therapeutics 20: 329–341 (1976).PubMedGoogle Scholar
  18. Greenblatt, D.J.; Comer, W.H.; Elliott, H.W.; Shader, R.I.; Knowles, J.A. and Ruelius, H.W.: Clinical pharmacokinetics of lorazepam. III. Intravenous injection. Preliminary results. Journal of Clinical Pharmacology 17: 490–494 (1977a).PubMedGoogle Scholar
  19. Greenblatt, D.J.; Joyce, T.H.: Comer, W.H.; Knowies, J.A.; Shader, R.I.; Kyriakopoulos, A.A.; MacLaughlin, D.S. and Ruelius, H.W.: Clinical pharmacokinetics of lorazepam. II. Intramuscular injection. Clinical Pharmacology and Therapeutics 21: 222–230 (1977b).PubMedGoogle Scholar
  20. Greenblatt, D.J.; Knowles, J.A.; Comer, W.H.; Shader, R.I.; Harmatz, J.S. and Ruelius, H.W.: Clinical pharmacokinetics of lorazepam. IV. Long-term oral administration. Journal of Clinical Pharmacology 17: 495–500 (1977c).PubMedGoogle Scholar
  21. Greenblatt, D.J.; Franke, K. and Shader, R.I.: Analysis of lorazepam and its glucuronide metabolite by electron-capture gas-liquid chromatography. Use in pharmacokinetic studies of lorazepam. Journal of Chromatography 146: 311–320 (1978).Google Scholar
  22. Greenblatt, D.J.; Shader, R.I.; Franke, K.; MacLaughlin, D.S.; Harmatz, J.S.; Allen, M.D.; Werner, A. and Woo, E.: Pharmacokinetics and bioavailability of intravenous, intramuscular, and oral lorazepam in humans. Journal of Pharmaceutical Sciences 68: 57–63 (1979a).PubMedCrossRefGoogle Scholar
  23. Greenblatt, D.J.; Allen, M.D.; Locniskar, A.; Harmatz, J.S. and Shader, R.I.: Lorazepam kinetics in the elderly. Clinical Pharmacology and Therapeutics 26: 103–113 (1979b).PubMedGoogle Scholar
  24. Greenblatt, D.J.; Allen, M.D.; MacLaughlin, D.S.; Huffman, D.H.; Harmatz, J.S. and Shader, R.I.: Single- and multipledose kinetics of oral lorazepam in humans: The predictability of accumulation. Journal of Pharmacokinetics and Biopharmaceutics 71: 159–179 (1979c).Google Scholar
  25. Greenblatt, D.J.; Divoll, M; Harmatz, J.S. and Shader, R.I.: Oxazepam kinetics: Effects of age and sex. Journal of Pharmacology and Experimental Therapeutics 215: 86–91 (1980a).PubMedGoogle Scholar
  26. Greenblatt, D.J.; Allen, M.D.; Harmatz, J.S. and Shader, R.I.: Diazepam disposition determinants. Clinical Pharmacology and Therapeutics 27: 301–312 (1980b).PubMedCrossRefGoogle Scholar
  27. Higuchi, S.; Urabe, H. and Shiobara, Y.: Simplified determination of lorazepam and oxazepam in biological fluids by gas chromatography-mass spectrometry. Journal of Chromatography 164: 55–61 (1979).PubMedCrossRefGoogle Scholar
  28. Howard, P.J.; Lilburn, J.K., Dundee, J.W.; Toner, W. and McIlroy, P.D.A.: Estimation of plasma lorazepam by gas-liquid chromatography and a benzene extraction. Anaesthesia 32: 767–770 (1977).PubMedCrossRefGoogle Scholar
  29. Johnson, R.F.; Schenker, S.; Roberts, R.K.; Desmond, P.V. and Wilkinson, G.R.: Plasma binding of benzodiazepines in humans. Journal of Pharmaceutical Sciences 68: 1320–1322 (1979).PubMedCrossRefGoogle Scholar
  30. Kabra, P.M.; Stevens, G.L. and Marton, L.J.: High-pressure liquid Chromatographic analysis of diazepam, oxazepam and N-desmethyldiazepam in human blood. Journal of Chromatography 150: 355–360 (1978).PubMedCrossRefGoogle Scholar
  31. Kangas, L.; Erkkola, R.; Kanto, J. and Eronen, M.: Transfer of free and conjugated oxazepam across the human placenta. European Journal of Clinical Pharmacology 17: 301–304 (1980).PubMedCrossRefGoogle Scholar
  32. Kellermann, G.H. and Luyten-Kellermann, M.: On the regulation of antipyrinc and oxazepam metabolism in man. Research Communications in Chemical Pathology and Pharmacology 23: 287–296 (1979).PubMedGoogle Scholar
  33. Klotz, U. and Reimann, I.: Delayed clearance of diazepam due to Cimetidine. New England Journal of Medicine 302: 1012–1014 (1980).PubMedCrossRefGoogle Scholar
  34. Knowles, J.A. and Ruelius, H.W.: Absorption and excretion of 7-chloro-1, 3-dihydro-3-hydroxy-5-phenyl-2H-1, 4-benzodiazepin-2-one (oxazepam) in humans. Determination of the drug by gas-liquid chromatography with electron capture detection. Arzneimittel-Forschung 22: 687–692 (1972).PubMedGoogle Scholar
  35. Knowles, J.A.; Comer, W.H. and Ruelius, H.W.: Disposition of 7-chloro-5-(o-chlorophenyl)-1,3-dihydro-3-hydroxy-2H-1,4-benzodiazepin-2-one (lorazepam) in humans. Determination of the drug by electron capture gas chromatography. Arzneimittel-Forschung 21: 1055–1059 (1971).PubMedGoogle Scholar
  36. Kraus, J.W.; Desmond, P.V.; Marshall, J.P.; Johnson, R.F.; Schenker, S. and Wilkinson, G.R.: Effects of aging and liver disease on disposition of lorazepam. Clinical Pharmacology and Therapeutics 24: 411–419 (1978).PubMedGoogle Scholar
  37. Kyriakopoulos, A.A.: Bioavailability of lorazepam in humans; in Gottschalk and Merlis (Eds) Pharmacokinetics of Psychoactive Drugs: Blood levels and clinical response, pp. 127–139 (Spectrum, New York 1976).Google Scholar
  38. Kyriakopoulos, A.A.; Greenblatt, D.J. and Shader, R.I.: Clinical pharmacokinetics of lorazepam: A review. Journal of Clinical Psychiatry 39 (No. 10, Sect. 2): 16–23 (1978).PubMedGoogle Scholar
  39. MacLeod, S.M.; Sellers, E.M.; Giles, H.G.; Billings, B.J.; Martin, P.R.; Greenblatt, D.J. and Marshman, J.A.: Interaction of disulfiram with benzodiazepines. Clinical Pharmacology and Therapeutics 24: 583–589 (1978).PubMedGoogle Scholar
  40. McBride, R.J.; Dundee, J.W.; Moore, J.; Toner, W. and Howard, P.J.: A study of the plasma concentrations of lorazepam in mother and neonate. British Journal of Anaesthesia 51: 971–977 (1979).PubMedCrossRefGoogle Scholar
  41. Melander, A.; Danielson, K.; Vessman, J. and Wåhlin, E.: Bioavailability of oxazepam: Absence of influence of food intake. Acta Pharmacologica et Toxicologica 40: 584–588 (1977).PubMedGoogle Scholar
  42. Ochs, H.R.; Busse, J.; Greenblatt, D.J. and Allen, M.D.: Entry of lorazepam into cerebrospinal fluid. British Journal of Clinical Pharmacology 10: 405–406 (1980).PubMedGoogle Scholar
  43. Odar-Cederlof, I.; Vessman, J.; Alvan, G. and Sjoqvist, F.: Oxazepam disposition in uremic patients. Acta Pharmacologica et Toxicologica 40(Suppl. 1): 52–62 (1977).PubMedGoogle Scholar
  44. Patwardhan, R.V.; Yarborough, G.W.; Desmond, P.V.; Johnson, R.F.; Schenker, S. and Speeg, K.V.: Cimetidine spares the glucuronidation of lorazepam and oxazepam. Gastroenterology 79: 912–916 (1980).PubMedGoogle Scholar
  45. Pilbrant, A.; Glenne, P.-O.; Sundwall, A.; Vessman, J. and Wretlind, M.: Comparative bioavailability of oral dosage forms of oxazepam — correlation with in vitro dissolution rate. Acta. Pharmacologica et Toxicologica 40(Suppl. 1): 7–15 (1977).PubMedGoogle Scholar
  46. Ruelius, H.W.: Comparative metabolism of lorazepam in man and four animal species. Journal of Clinical Psychiatry 39 (No. 10, Sect. 2): 11–15 (1978).PubMedGoogle Scholar
  47. Sadee, W. and van der Kleijn, E.: Thermolysis of 1,4-benzodiazepines during gas chromatography and mass spectroscopy. Journal of Pharmaceutical Sciences 60: 135–137 (1971).PubMedCrossRefGoogle Scholar
  48. Sellers, E.M.; Giles, H.G.; Greenblatt, D.J. and Naranjo, C.A.: Differential effects on benzodiazepine disposition by disulfiram and ethanol. Arzneimittel-Forschung 30: 882–886 (1980).PubMedGoogle Scholar
  49. Sellers, E.M.; Greenblatt, D.J.; Giles, H.G.; Naranjo, C.A.; Kaplan, H. and MacLeod, S.M.: Chlordiazepoxide and oxazepam disposition in cirrhosis. Clinical Pharmacology and Therapeutics 26: 240–246 (1979).PubMedGoogle Scholar
  50. Shull, H.J.; Wilkinson, G.R.; Johnson, R. and Schenker, S.: Normal disposition of oxazepam in acute viral hepatitis and cirrhosis. Annals of Internal Medicine 84: 420–425 (1976).PubMedGoogle Scholar
  51. Tomson, G.; Lunell, N.-O.; Sundwall, A. and Rane, A.: Placental passage of oxazepam and its metabolism in mother and newborn. Clinical Pharmacology and Therapeutics 25: 74–81 (1979).PubMedGoogle Scholar
  52. Verbeeck, R.; Tjandramaga, T.B.; Verberckmoes, R. and de Schepper, P.J.: Biotransformation and excretion of lorazepam in patients with chronic renal failure. British Journal of Clinical Pharmacology 3: 1033–1039 (1976).PubMedCrossRefGoogle Scholar
  53. Vessman, J.; Alexander, B.; Sjoqvist, F.; Strindberg, B. and Sundwall, A.: Comparative pharmacokinetics of oxazepam and nortriptyline after single oral doses in man; in Garratini et al. (Eds) The Benzodiazepines, pp. 165–173 (Raven Press, New York 1973).Google Scholar
  54. Vessman, J.; Freij, G. and Stromberg, S.: Determination of oxazepam in serum and urine by electron capture gas chromatography. Acta Pharmaceutica Suecica 9: 447–456 (1972).PubMedGoogle Scholar
  55. Vessman, J.; Johansson, M.; Magnusson, P. and Stromberg, S.: Determination of intact oxazepam by electron capture gas chromatography after an extractive alkylation reaction. Analytical Chemistry 49: 1545–1549 (1977).PubMedCrossRefGoogle Scholar
  56. Vree, T.B.; Baars, A.M.; Hekster, Y.A. and van der Kleijn, E.: Simultaneous determination of diazepam and its metabolites N-desmethyldiazepam, oxydiazepam and oxazepam in plasma and urine of man and dog by means of high-performance liquid chromatography. Journal of Chromatography 162: 605–614 (1979).PubMedCrossRefGoogle Scholar
  57. Wilkinson, G.R.: The effects of liver disease and aging on the disposition of diazepam, chlordiazepoxide, oxazepam, and lorazepam in man. Acta Psychiatrica Scandinavica 274 (Suppl.): 56–74 (1978).PubMedCrossRefGoogle Scholar
  58. Wretlind, M.; Pilbrant, A.; Sundwall, A. and Vessman, J.: Disposition of three benzodiazepines after single oral administration in man. Acta Pharmacologica et Toxicologica 40 (Suppl. 1): 28–39 (1977).Google Scholar

Copyright information

© ADIS Press Australasia Pty Ltd. 1981

Authors and Affiliations

  • David J. Greenblatt
    • 1
  1. 1.Division of Clinical Pharmacology, Departments of Psychiatry and MedicineTufts University School of Medicine and New England Medical Center HospitalUSA

Personalised recommendations