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Clinical Pharmacokinetics of Oxazepam and Lorazepam

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Summary

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%).

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References

  • 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).

    Article  CAS  Google Scholar 

  • 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).

    PubMed  CAS  Google Scholar 

  • Alvan, G.; Siwers, B. and Vessman, J.: Pharmacokinetics of oxazepam in healthy volunteers. Acta Pharmacologica et Toxicologica 40 (Suppl. 1): 40–51 (1977).

    PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • de Groot, G.; Maes, R.A.A.; Defoort, P. and Thiery, M.: Placental transfer of lorazepam. 1CRS Medical Science 3: 594 (1975).

    Google Scholar 

  • 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).

    Article  PubMed  Google Scholar 

  • 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).

    Article  PubMed  Google Scholar 

  • 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).

    PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • Elliott, H.W.: Metabolism of lorazepam. British Journal of Anaesthesia 48: 1017–1023 (1976).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • Frigerio, A.; Baker, K.M. and Belvedere, G.: Gas Chromatographic degradation of several drugs and their metabolites. Analytical Chemistry 45: 1846–1851 (1973).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    CAS  Google Scholar 

  • Greenblatt, D.J. and Koch-Weser, J.: Intramuscular injection of drugs. New England Journal of Medicine 295: 542–546 (1976).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    PubMed  CAS  Google Scholar 

  • 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).

    PubMed  CAS  Google Scholar 

  • 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).

    PubMed  CAS  Google Scholar 

  • 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).

    PubMed  CAS  Google Scholar 

  • 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).

    PubMed  CAS  Google Scholar 

  • 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).

    CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    PubMed  CAS  Google Scholar 

  • 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 

  • 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).

    PubMed  CAS  Google Scholar 

  • Greenblatt, D.J.; Allen, M.D.; Harmatz, J.S. and Shader, R.I.: Diazepam disposition determinants. Clinical Pharmacology and Therapeutics 27: 301–312 (1980b).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    PubMed  CAS  Google Scholar 

  • Klotz, U. and Reimann, I.: Delayed clearance of diazepam due to Cimetidine. New England Journal of Medicine 302: 1012–1014 (1980).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    PubMed  CAS  Google Scholar 

  • 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).

    PubMed  CAS  Google Scholar 

  • 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).

    PubMed  CAS  Google Scholar 

  • 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 

  • 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).

    PubMed  CAS  Google Scholar 

  • 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).

    PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    PubMed  CAS  Google Scholar 

  • 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).

    PubMed  CAS  Google Scholar 

  • 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).

    PubMed  Google Scholar 

  • 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).

    PubMed  CAS  Google Scholar 

  • 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).

    PubMed  CAS  Google Scholar 

  • 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).

    PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    PubMed  CAS  Google Scholar 

  • 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).

    PubMed  CAS  Google Scholar 

  • 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).

    PubMed  CAS  Google Scholar 

  • 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).

    PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • 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 

  • 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).

    PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • 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 

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  1. Division of Clinical Pharmacology, Departments of Psychiatry and Medicine, Tufts University School of Medicine and New England Medical Center Hospital, Box 1007, 171 Harrison Avenue, Boston, Mass., 02111, USA

    David J. Greenblatt

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Greenblatt, D.J. Clinical Pharmacokinetics of Oxazepam and Lorazepam. Clin Pharmacokinet 6, 89–105 (1981). https://doi.org/10.2165/00003088-198106020-00001

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