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Clinical Pharmacokinetics

, Volume 3, Issue 5, pp 381–394 | Cite as

Clinical Pharmacokinetics of Chlordiazepoxide

  • David J. Greenblatt
  • Richard I. Shader
  • Stuart M. MacLeod
  • Edward M. Sellers
Article

Summary

Chlordiazepoxide was the first benzodiazepine derivative made available for clinical use. The metabolic pathway of chlordiazepoxide is complex, since the drug is biolransformed into a succession of pharmacologically active products: desmethylchlordiazepoxide, demoxepam, desmethyldiazepam, and oxazepam. The elimination half-life (t1/2β) chlordiazepoxide following single doses in healthy individuals generally ranges from 5 to 30 hours, and the volume of distribution from 0.25 to 0.50 liters/kg. The hepatic extraction ratio is well under 5 %. Elimination of the parent compound is mirrored by formation of the first active metabolite.

Clearance of chlordiazepoxide is reduced and (t1/2β) is prolonged in the elderly, in those with cirrhosis, and in those receiving concurrent disulfiram therapy. Oral chlordiazepoxide is rapidly and completely absorbed, but intramuscular injection is painful and results in slow and erratic absorption. Multiple-dose therapy with chlordiazepoxide results in accumulation of the parent compound, as well as two or more of its active metabolites. The rate and extent of accumulation varies considerably between individuals.

A relation between plasma concentrations of chlordiazepoxide and its metabolites to clinical effects has been suggested in some studies and is currently under further investigation.

Keywords

Chlordiazepoxide Clinical Pharmacokinetic Oxazepam Steady State Plasma Concentration Single 25mg Oral Dose 
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.

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References

  1. Bond, A.J.; Hailey, D.M. and Lader, M.H.: Plasma concentrations of benzodiazepines. British Journal of Clinical Pharmacology 4: 51–56 (1977).PubMedCrossRefGoogle Scholar
  2. Boston Collaborative Drug Surveillance Program: Clinical depression of the central nervous system due to diazepam and chlordiazepoxide in relation to cigarette smoking and age. New England Journal of Medicine 288: 277–280 (1973).CrossRefGoogle Scholar
  3. Boxenbaum, H.G.; Geitner, K.A.; Jack, M.L.; Dixon, W.R. and Kaplan, S.A.: Pharmacokinetic and biopharmaceutic profile of chlordiazepoxide HC1 in healthy subjects: Multiple-dose oral administration. Journal of Pharmacokinetics and Biopharmaceutics 5: 25–39 (1977b).PubMedGoogle Scholar
  4. Boxenbaum, H.G.; Geitner, K.A.; Jack, M.L.; Dixon, W.R.; Spiegel, H.E.; Symington, J.; Christian, R.; Moore, J.D.; Weissman, L. and Kaplan, S.A.: Pharmacokinetic and biopharmaceutic profile of chlordiazepoxide HC1 in healthy subjects: Single-dose studies by the intravenous, intramuscular, and oral routes. Journal of Pharmacokinetics and Biopharmaceutics 5: 3–23 (1977a).PubMedGoogle Scholar
  5. Crooks, J.; O’Malley, K. and Stevenson, I.H.: Pharmacokinetics in the elderly. Clinical Pharmacokinetics 1: 280–296 (1976).PubMedCrossRefGoogle Scholar
  6. Decancq, H.G. Jr.; Bosco, J.R. and Townsend, E.H. Jr.: Chlordiazepoxide in labor. Journal of Pediatrics 67: 836–840 (1965).PubMedCrossRefGoogle Scholar
  7. deSilva, 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).CrossRefGoogle Scholar
  8. Dixon, R.; Brooks, M.A.; Postma, E.; Hackman, M.R.; Spector, S.; Moore, J.D. and Schwartz, M.A.: N-desmethyldiazepam: a new metabolite of chlordiazepoxide in man. Clinical Pharmacology and Therapeutics 20: 450–457 (1976).PubMedGoogle Scholar
  9. Ferguson, J.L. and Couri, D.: Electron capture gas chromatography determination of benzodiazepines and metabolites. Journal of Analytical Toxicology 1: 171–174 (1977).Google Scholar
  10. Gottschalk, L.A.; Biener, R. and Dinovo, E.C.: Effects of oral and intramuscular routes of administration on serum chlordiazepoxide levels and the prediction of these levels from predrug fasting serum glucose concentrations. Research Communications in Chemical Pathology and Pharmacology 8: 697–702 (1974).PubMedGoogle Scholar
  11. Gottschalk, L.A. and Kaplan, S.A.: Chlordiazepoxide plasma levels and clinical responses. Comprehensive Psychiatry 13: 519–527 (1972).PubMedCrossRefGoogle Scholar
  12. Greenblatt, D.J.; Harmatz, J.S.; Stanski, D.R.; Shader, R.I.; Franke, K. and Koch-Weser, J.: Factors influencing blood concentrations of chlordiazepoxide: A use of multiple regression analysis. Psychopharmacology 54: 277–282 (1977c).PubMedCrossRefGoogle Scholar
  13. Greenblatt, D.J. and Koch-Weser, J.: Clinical pharmacokinetics. New England Journal of Medicine 293: 702–705, 964-970 (1975).PubMedCrossRefGoogle Scholar
  14. Greenblatt, D.J. and Shader, R.I.: Benzodiazepines in Clinical Practice (Raven Press, New York 1974).Google Scholar
  15. Greenblatt, D.J.; Shader, R.I.; Franke, K. and Harmatz, J.S.: Pharmacokinetics of chlordiazepoxide and metabolites following single and multiple oral doses. International Journal of Clinical Pharmacology and Biopharmacy. In press (1978b).Google Scholar
  16. Greenblatt, D.J.; Shader, R.I.; Franke, K.; MacLaughlin, D.S.; Ransil, B.J. and Kock-Weser, J.: Kinetics of intravenous chlordiazepoxide: sex differences in drug distribution. Clinical Pharmacology and Therapeutics 22: 893–903 (1977a).PubMedGoogle Scholar
  17. Greenblatt, D.J.; Shader, R.I.; Harmatz, J.S.; Franke, K. and Koch-Weser, J.: Influence of magnesium and aluminium hydroxide mixture on chlordiazepoxide absorption. Clinical Pharmacology and Therapeutics 19: 234–239 (1976b).PubMedGoogle Scholar
  18. Greenblatt, D.J.; Shader, R.I.; Harmatz, J.S.; Franke, K. and Koch-Weser, J.: Absorption rate, blood concentrations, and early response to oral chlordiazepoxide. American Journal of Psychiatry 134: 559–562 (1977b).PubMedGoogle Scholar
  19. Greenblatt, D.J.; Shader, R.I. and Koch-Weser, J.: Pharmacokinetic determinants of the response to single doses of chlordiazepoxide. American Journal of Psychiatry 131: 1395–1397 (1974b).PubMedGoogle Scholar
  20. Greenblatt, D.J.; Shader, R.I. and Koch-Weser, J.: Serum creatine Phosphokinase concentrations after intramuscular chlordiazepoxide and its solvent. Journal of Clinical Pharmacology 16: 118–121 (1976a).PubMedGoogle Scholar
  21. Greenblatt, D.J.; Shader, R.I.; Koch-Weser, J. and Franke, K.: Slow absorption of intramuscular chlordiazepoxide. New England Journal of Medicine 291: 1116–1118 (1974a).PubMedCrossRefGoogle Scholar
  22. Greenblatt, D.J.; Shader, R.I.; MacLeod, S.M.; Sellers, E.M.; Franke, K. and Giles, H.G.: Absorption of oral and intramuscular chlordiazepoxide. European Journal of Clinical Pharmacology. In press (1978a).Google Scholar
  23. Greizerstein, H.B. and Wojtowicz, C.: Simultaneous determination of chlordiazepoxide and its N-demethyl metabolite in 50-Mu-L blood samples by high pressure liquid chromatography. Analytical Chemistry 49: 2235–2236 (1977).PubMedCrossRefGoogle Scholar
  24. Hackman, M.R.; Brooks, M.A. and deSilva, J.A.F.: Determination of chlordiazepoxide hydrochloride (Librium) and its major metabolites in plasma by differential pulse polarography. Analytical Chemistry 46: 1075–1082 (1974).PubMedCrossRefGoogle Scholar
  25. Koechlin, B.A. and D’Arconte, L.: Determination of chlordiazepoxide (Librium) and of a metabolite of lactam character in plasma of humans, dogs, and rats by a specific spectrofluorometric micro method. Analytical Biochemistry 5: 195–207 (1963).PubMedCrossRefGoogle Scholar
  26. Koechlin, B.A.; Schwartz, M.A.; Krol, G. and Oberhansli, W.: The metabolic fate of C14-labeled chlordiazepoxide in man, in the dog, and in the rat. Journal of Pharmacology and Experimental Therapeutics 148: 399–411 (1965)PubMedGoogle Scholar
  27. Lin, K.-M. and Friedel, R.O.: Relationship of plasma levels of chlordiazepoxide and metabolites to clinical response. American Journal of Psychiatry. In press (1978).Google Scholar
  28. Linnoila, M.; Otterstrom, S. and Anttila, M.: Serum chlordiazepoxide, diazepam and thioridazine concentrations after the simultaneous ingestion of alcohol or placebo drink. Annals of Clinical Research 6: 4–6 (1974).PubMedGoogle Scholar
  29. MacDonald, A.; Michaelis, A.F. and Senkowski, B.Z.: Chlordiazepoxide; in Florey (Ed) Analytical Profiles of Drug Substances, Vol. 1, p. 15–37 (Academic Press, New York, 1972b).CrossRefGoogle Scholar
  30. MacDonald, A.; Michaelis, A.F. and Senkowski, B.Z.: Chlordiazepoxide hydrochloride; in Florey (Ed) Analytical Profiles of Drug Substances, Vol. 1, p. 39–51 (Academic Press, New York, 1972a).CrossRefGoogle Scholar
  31. MacLeod, S.M.; Greenblatt, D.J. and Sellers, E.M.: Determination of intravenous chlordiazepoxide (CDX) pharmacokinetics: plasma versus blood. Clinical Research 25: 273A (1977).Google Scholar
  32. Randall, L.O. and Kappell, B.: Pharmacological activity of some benzodiazepines and their metabolites; in Garattini, Mussini and Randall (Eds) The Benzodiazepines, p. 27–51 (Raven Press, New York, 1973).Google Scholar
  33. Randall, L.O.; Schallek, W.; Heise, G.A.; Keith, E.F. and Bagdon, R.E.: The psychosedative properties of methaminodiazepoxide. Journal of Pharmacology and Experimental Therapeutics 129: 163–171 (1960).PubMedGoogle Scholar
  34. Roberts, R.K.; Wilkinson, G.R.; Branch, R.A. and Schenker, S.: Effect of age and cirrhosis on the disposition and elimination of chlordiazepoxide (Librium). Gastroenterology 73: A45/1243 (1977).Google Scholar
  35. 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
  36. Schwartz, M.A. and Postma, E.: Metabolic N-demethylation of chlordiazepoxide. Journal of Pharmaceutical Sciences 55: 1358–1362 (1966).CrossRefGoogle Scholar
  37. Schwartz, M.A. and Postma, E.: Metabolites of demoxepam, a chlordiazepoxide metabolite, in man. Journal of Pharmaceutical Sciences 61: 123–125 (1972).PubMedCrossRefGoogle Scholar
  38. Schwartz, M.A.; Postma, E. and Gaut, Z.: Biological half-life of chlordiazepoxide and its metabolite, demoxepam, in man. Journal of Pharmaceutical Sciences 60: 1500–1503 (1971).PubMedCrossRefGoogle Scholar
  39. Sellers, E.M.; MacLeod, S.M. and Greenblatt, D.J.: Unpublished data (1978).Google Scholar
  40. Sellers, E.M.; MacLeod, S.M.; Greenblatt, D.J. and Giles, H.G.: Inhibition of chlordiazepoxide biotransformation by disulfiram. Clinical Research 24: 652A (1976).Google Scholar
  41. Sellers, E.M.; MacLeod, S.M.; Greenblatt, D.J. and Giles, H.G.: Influence of disulfiram and disease on benzodiazepine disposition. Clinical Pharmacology and Therapeutics 21: 117 (1977).Google Scholar
  42. Shader, R.I.; Greenblatt, D.J.; Harmatz, J.S.; Franke, K. and Koch-Weser, J.: Absorption and disposition of chlordiazepoxide in young and elderly male volunteers. Journal of Clinical Pharmacology 17: 709–718 (1977).PubMedGoogle Scholar
  43. Smith, T.C. and Moyer, C.E.: Bioavailability of two preparations of chlordiazepoxide. Current Therapeutic Research 20: 204–210 (1976).PubMedGoogle Scholar
  44. Stanski, D.R.; Greenblatt, D.J., Selwyn, A.; Shader, R.I.; Franke, K. and Koch-Weser, J.: Plasma and cerebrospinal fluid concentrations of chlordiazepoxide and its metabolites in surgical patients. Clinical Pharmacology and Therapeutics 20: 571–578 (1976).PubMedGoogle Scholar
  45. Sternbach, L.H.; Koechlin, B.A. and Reeder, E.; Quinazolines and 1,4-benzodiazepines. (VIII). The photoisomerization of 7-chloro-2-methylamino-5-phenyl-3H-1,4-benzodiazepine 4-oxide. Journal of Organic Chemistry 27: 4671–4672 (1962).CrossRefGoogle Scholar
  46. Stewart, J.T. and Williamson, J.L.: Fluorometric determination of chlordiazepoxide in dosage forms and biological fluids with fluorescamine. Analytical Chemistry 48: 1182–1185 (1976).PubMedCrossRefGoogle Scholar
  47. Strojny, N.; Bratin, K.; Brooks, M.A. and deSilva, J.A.F.: Determination of chlordiazepoxide, diazepam, and their major metabolites in blood or plasma by spectrophotodensitometry. Journal of Chromatography 143: 363–374 (1977).CrossRefGoogle Scholar
  48. Zingales, I.A.: Determination of chlordiazepoxide plasma concentrations by electron capture gas-liquid chromatography. Journal of Chromatography 61: 237–252 (1971).PubMedCrossRefGoogle Scholar

Copyright information

© ADIS Press 1978

Authors and Affiliations

  • David J. Greenblatt
    • 1
  • Richard I. Shader
    • 2
  • Stuart M. MacLeod
    • 2
  • Edward M. Sellers
    • 3
  1. 1.Clinical Pharmacology UnitMassachusetts General HospitalBostonUSA
  2. 2.Psychopharmacology Research LaboratoryMassachusetts Mental Health CenterBostonUSA
  3. 3.Clinical InstituteAddiction Research FoundationTorontoUSA

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