Skip to main content
SpringerLink
Log in

Pharmacokinetic and biopharmaceutic profile of chlordiazepoxide HCl in healthy subjects: Single-dose studies by the intravenous, intramuscular, and oral routes

  • Published:
Journal of Pharmacokinetics and Biopharmaceutics Aims and scope Submit manuscript

Abstract

Single 30- mg doses of chlordiazepoxide HCl were administered to six healthy human subjects by the intravenous, oral, and intramuscular routes. Plasma concentration- time curves following intravenous administration were satisfactorily described by a biexponential equation consistent with a two-compartment open model system. Mean values of half-lives for the so-called distribution and elimination phases were 0.252 and 9.39 hr, respectively. The mean values for the volume of the central compartment (V 1) and volume of distribution\((V_{d_\beta } )\) were 18.0 and 30.9% of body weight, respectively. Following oral administration, the drug was rapidly and completely absorbed. Absorption was first order (t1/2≈27 min), and three of the six subjects showed a discernible lag time of approximately 20 min. Drug absorption following intramuscular administration was comparatively slow. A two- compartment “muscle model” comprised of precipitated and solubilized drug in the muscle was found to satisfactorily characterize the absorption process following administration by this route.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. L. H. Sternbach. The discovery of Librium.Agents and Actions 2:193–196 (1972).

    Article  CAS  PubMed  Google Scholar 

  2. Physicians' Desk Reference, 29th ed., Medical Economics Co., Oradell, N.J., 1975, p. 1245.

  3. C. Abruzzo, I. Bekersky, S. Cotler, C. Coutinho, R. Lucek, and V. Toome. Data on file, Hoffmann-La Roche Inc., Nutley, N.J.

  4. T. Fujita, J. Iwasa, and C. Hansch. A new substituent constant,π, derived from partition coefficients.J. Am. Chem. Soc. 86:5175–5180 (1964).

    Article  CAS  Google Scholar 

  5. T. C. McIlvaine. A buffer solution for colorimetric comparison.J. Biol. Chem. 49:183–186 (1921); throughDocumenta Geigy Scientific Tables, 7th ed. (K. Diem and C. Lentner, eds.), Ciba-Geigy Ltd., Basel, Switzerland, 1970, pp. 280–282.

    CAS  Google Scholar 

  6. R. A. Giannella, S. A. Broitman, and N. Zamcheck. Gastric acid barrier to ingested microorganisms in man: Studiesin vivo andin vitro.Gut 13:251–256 (1972).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. S. A. Kaplan and S. Cotler. Use of cannulated everted intestinal sac for serial sampling as a drug absorbability (permeability) screen.J. Pharm. Sci. 61:1361–1365 (1972).

    Article  CAS  PubMed  Google Scholar 

  8. A. H. Anton. The relation between the binding of sulfonamides to albumin and their antibacterial efficacy.J. Pharmacol. Exp. Ther. 129:282–290 (1960).

    CAS  PubMed  Google Scholar 

  9. M. Rowland. Influence of route of administration on drug availability.J. Pharm. Sci. 61:70–74 (1972).

    Article  CAS  PubMed  Google Scholar 

  10. M. A. Schwartz. Pathways of metabolism of the benzodiazepines. In S. Garattini, E. Mussini, and L. O. Randall (eds.),The Benzodiazepines, Raven Press, New York, 1973, pp. 53–74.

    Google Scholar 

  11. W. R. Dixon, M. A. Brooks, E. Postma, M. R. Hackman, and M. A. Schwartz. Identification and determination ofN-desmethyl-diazepam in plasma following chronic administration of chlordiazepoxide hydrochloride (Librium) to man.Fed. Proc. 33:472, Part I (1974).

    Google Scholar 

  12. S. A. Kaplan, M. Lewis, M. A. Schwartz, E. Postma, S. Cotler, C. W. Abruzzo, T. L. Lee, and R. E. Weinfeld. Pharmacokinetic model for chlordiazepoxide-HCl in the dog.J. Pharm. Sci. 59:1569–1574 (1970).

    Article  CAS  PubMed  Google Scholar 

  13. M. A. Schwartz and E. Postma. MetabolicN-demethylation of chlordiazepoxide.J. Pharm. Sci. 55:1358–1362 (1966).

    Article  CAS  Google Scholar 

  14. M. A. Schwartz, E. Postma, and Z. Gaut. Biological half-life of chlordiazepoxide and its metabolite, demoxepam, in man.J. Pharm. Sci. 60:1500–1503 (1971).

    Article  CAS  PubMed  Google Scholar 

  15. L. A. Gottschalk, R. Biener, and E. C. Dinovo. Effect of oral and intramuscular routes of administration on serum chlordiazepoxide levels and the prediction of these levels from predrug fasting serum glucose concentrations.Res. Commun. Chem. Pathol. Pharmacol. 8:697–702 (1974).

    CAS  PubMed  Google Scholar 

  16. D. J. Greenblatt, R. I. Shader, and J. Koch-Weser. Slow absorption of intramuscular chlordiazepoxide.New Engl. J. Med. 291:1116–1118 (1974).

    Article  CAS  PubMed  Google Scholar 

  17. D. J. Greenblatt, R. I. Shader, and J. Koch-Weser. Pharmacokinetic determinants of the response to single doses of chlordiazepoxide.Am. J. Psychiat. 131:1395–1397 (1974).

    CAS  PubMed  Google Scholar 

  18. D. J. Greenblatt, R. I. Shader, J. Koch-Weser, and K. Franke. Clinical pharmacokinetics of chlordiazepoxide.Psychopharmacol. Bull. 11(4):34–35 (1975).

    CAS  PubMed  Google Scholar 

  19. D. J. Greenblatt, R. I. Shader, K. Franke, and J. Koch-Weser. Pharmacokinetics of intravenous chlordiazepoxide.Clin. Pharmacol. Ther. 17:235 (1975).

    Google Scholar 

  20. D. J. Greenblatt, R. I. Shader, J. S. Harmatz, K. Franke, and J. Koch-Weser. Influence of magnesium and aluminium hydroxide mixture on chlordiazepoxide absorption.Clin. Pharmacol. Ther. 19:234–239 (1976).

    CAS  PubMed  Google Scholar 

  21. L. Z. Benet. General treatment of linear mammillary models with elimination from any compartment as used in pharmacokinetics.J. Pharm. Sci. 61:536–541 (1972).

    Article  CAS  PubMed  Google Scholar 

  22. C. M. Metzler, G. L. Elfring, and A. J. McEwen.A User's Manual for NONLIN and Associated Programs, Upjohn Co., Kalamazoo, Mich., April 20, 1974.

    Google Scholar 

  23. H. O. Hartley. The modified Gauss-Newton method for the fitting of non-linear regression functions.Technometrics 3:269–280 (1961).

    Article  Google Scholar 

  24. A. J. Sedman and J. G. Wagner. CSTRIP, a Fortran IV computer program for obtaining initial polyexponential parameter estimates.J. Pharm. Sci. 65:1006–1010 (1975).

    Article  Google Scholar 

  25. H. G. Boxenbaum, S. Riegelman, and R. M. Elashoff. Statistical estimations in pharmacokinetics.J. Pharmacokin. Biopharm. 2:123–148 (1974).

    Article  CAS  Google Scholar 

  26. S. Riegelman, J. C. K. Loo, and M. Rowland. Shortcomings in pharmacokinetic analysis by conceiving the body to exhibit properties of a single compartment.J. Pharm. Sci. 57:117–123 (1968).

    Article  CAS  PubMed  Google Scholar 

  27. A. Rescigno and G. Segre.Drug and Tracer Kinetics, Blaisdell, Waltham, Mass., 1966, pp. 91–94.

    Google Scholar 

  28. W. G. Kramer, R. P. Lewis, T. C. Cobb, W. F. Forester, Jr., J. A. Visconti, L. A. Wanke, H. G. Boxenbaum, and R. H. Reuning. Pharmacokinetics of digoxin: Comparison of a two- and a three-compartment model in man.J. Pharmacokin. Biopharm. 2:299–312 (1974).

    Article  CAS  Google Scholar 

  29. J. G. Wagner.Biopharmaceutics and Relevant Pharmacokinetics, Drug Intelligence Publications, Hamilton, Ill., 1971, p. 295.

    Google Scholar 

  30. S. Riegelman, J. Loo, and M. Rowland. Concept of a volume of distribution and possible errors in evaluation of this parameter.J. Pharm. Sci. 57:128–133 (1968).

    Article  CAS  PubMed  Google Scholar 

  31. M. Gibaldi, R. Nagashima, and G. Levy. Relationship between the drug concentration in plasma or serum and amount of drug in the body.J. Pharm. Sci. 58:193–197 (1969).

    Article  CAS  Google Scholar 

  32. M. Gibaldi and D. Perrier. Drug elimination and apparent volume of distribution in multicompartment systems.J. Pharm. Sci. 61:952–954 (1972).

    Article  CAS  PubMed  Google Scholar 

  33. C. V. Greenway and R. D. Stark. Hepatic vascular bed.Physiol. Rev. 51:23–65 (1971).

    CAS  PubMed  Google Scholar 

  34. A. E. Till, L. Z. Benet, and K. C. Kwan. An integrated approach to the pharmacokinetic analysis of drug absorption.J. Pharmacokin. Biopharm. 2:525–544 (1974).

    Article  CAS  Google Scholar 

  35. J. C. K. Loo and S. Riegelman. New method for calculating the intrinsic absorption rate of drugs.J. Pharm. Sci. 57:918–928 (1968).

    Article  CAS  PubMed  Google Scholar 

  36. H. G. Boxenbaum and S. A. Kaplan. Potential source of error in absorption rate calculations.J. Pharmacokin. Biopharm. 3:257–264 (1975).

    Article  CAS  Google Scholar 

  37. M. Berman. The formulation and testing of models.Ann. N.Y. Acad. Sci. 108:182–194 (1963).

    Article  CAS  PubMed  Google Scholar 

  38. J. G. Wagner. Intrasubject variation in elimination half-lives of drugs which are appreciably metabolized.J. Pharmacokin. Biopharm. 1:165–173 (1973).

    Article  CAS  Google Scholar 

  39. W. J. Westlake. Problems associated with analysis of pharmacokinetic models.J. Pharm. Sci. 60:882–885 (1971).

    Article  CAS  PubMed  Google Scholar 

  40. W. J. Waddell and T. C. Butler. Calculation of intracellular pH from the distribution of 5,5-dimethyl-2,4-oxazolidinedione (DMO): Application to skeletal muscle of the dog.J. Clin. Invest. 38:720–729 (1959).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. E. D. Robin, R. J. Wilson, and P. A. Bromberg. Intracellular acid-base relations and intracellular buffers.Ann. N.Y. Acad. Sci. 92:539–546 (1961).

    Article  CAS  PubMed  Google Scholar 

  42. W. O. Fenn. Carbon dioxide and intracellular homeostasis.Ann. N. Y. Acad. Sci. 92:547–558 (1961).

    Article  CAS  PubMed  Google Scholar 

  43. H. G. Boxenbaum, K. A. Geitner, M. L. Jack, W. R. Dixon, and S. A. Kaplan. Pharmacokinetic and biopharmaceutic profile of chlordiazepoxide HCl in healthy subjects: Multiple-dose oral administration.J. Pharmacokin. Biopharm. 5:25–39 (1977).

    Article  CAS  Google Scholar 

  44. H. B. Kostenbauder, R. P. Rapp, J. P. McGovren, T. S. Foster, D. G. Perrier, H. M. Blacker, W. C. Hulon, and A. W. Kinkel. Bioavailability and single-dose pharmacokinetics of intramuscular phenytoin.Clin. Pharmacol. Ther. 18:449–456 (1975).

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Hoffmann-La Roche Inc., 07110, Nutley, New Jersey

    H. G. Boxenbaum, K. A. Geitner, M. L. Jack, W. R. Dixon, H. E. Spiegel, J. Symington, R. Christian, L. Weissman & S. A. Kaplan

  2. Deer Lodge Research Unit, 59722, Deer Lodge, Montana

    J. D. Moore

Authors
  1. H. G. Boxenbaum
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. K. A. Geitner
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M. L. Jack
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. W. R. Dixon
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. H. E. Spiegel
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J. Symington
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. R. Christian
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. J. D. Moore
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. L. Weissman
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. S. A. Kaplan
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Boxenbaum, H.G., Geitner, K.A., Jack, M.L. et al. Pharmacokinetic and biopharmaceutic profile of chlordiazepoxide HCl in healthy subjects: Single-dose studies by the intravenous, intramuscular, and oral routes. Journal of Pharmacokinetics and Biopharmaceutics 5, 3–23 (1977). https://doi.org/10.1007/BF01064806

Download citation

  • Received:

  • Revised:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01064806

Key words

Search

Navigation