Skip to main content
SpringerLink
Log in

Prediction of hepatic first-pass metabolism and plasma levels following intravenous and oral administration of barbiturates in the rabbit based on quantitative structure—Pharmacokinetic relationships

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

Abstract

Based on the concept of physiological pharmacokinetics, the hepatic first-pass metabolism and plasma levels following intravenous and oral administration of barbiturates in the rabbit was predicted based on the relationships between principle kinetic parameters and lipophilicity (chloroform-water partition coefficient). Good log-log linear relationships between kinetic parameters and lipophilicity were obtained for the seven barbiturates examined. The values of correlation coefficient were improved slightly by using the corrected values for partition coefficients of nonionic molecules in the cases of principle parameters such as drug-protein and drug-blood cell affinity, intrinsic hepatic clearance, and unbound volume of distribution. There was also a good linear relationship between absorption rate constant (mean absorption time) and lipophilicity. The mean hepatic transit time was negligible for the most lipophilic drug (hexobarbital) examined; this suggests that the mean absorption time for these barbiturates does reflect the absorption process. The available fraction in relation to hepatic first-pass metabolism was well predicted from the lipophilicity by both well-stirred and parallel-tube models, and the difference in the values predicted by both models was minimal. There were good relationships between predicted and observed values for plasma levels after intravenous and oral administration, except for two (cyclobarbital and phenobarbital) of the seven drugs used. The great difference between predicted and observed values for these two drugs was considered due to substituent effects in liver metabolism.

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. J. K. Seydel, D. Trettin, and H. P. Cordes. Quantitative structure-pharmacokinetic relationships derived on antibacterial sulfonamides in rats and its comparison to quantitative structure-activity relationships.J. Med. Chem. 23:607–613 (1980).

    Article  CAS  PubMed  Google Scholar 

  2. C. Hansch. A quantitative approach to biochemical structure-activity relationships.Accounts Chem. Res. 2:232–239 (1969).

    Article  CAS  Google Scholar 

  3. C. Hansch and T. Fujita.ρ-σ-χ analysis. A method for the correlation of biological activity and chemical structure.J. Am. Chem. Soc. 86:1616–1626 (1964).

    Article  CAS  Google Scholar 

  4. G. Levy. Kinetics of pharmacologic efiects.Clin. Pharmacol. Ther. 7:362–372 (1966).

    CAS  PubMed  Google Scholar 

  5. S. Toon and M. Rowland. Quantitative structure pharmacokinetic activity relationship with some tetracyclines.J. Pharm. Pharmacol. 31:(suppl.):43P (1979).

    Google Scholar 

  6. S. Toon and M. Rowland. Structure-pharmacokinetic relationships among the barbiturates in the rat.J. Pharmacol. Exp. Ther. 225:752–763 (1983).

    CAS  PubMed  Google Scholar 

  7. A. E. Bird and A. C. Marshall. Correlation of serum binding of penicillins with partition coefficients.Biochem. Pharmacol. 16:2275–2290 (1967).

    Article  CAS  PubMed  Google Scholar 

  8. J. B. Houston, D. G. Upshall, and J. W. Bridges. Further studies using carbamate esters as model compounds to investigate the role of lipophilicity in the gastrointestinal absorption of foreign compounds.J. Pharmacol. Exp. Ther. 195:67–72 (1975).

    CAS  PubMed  Google Scholar 

  9. Y.-J. Lin, S. Awazu, M. Hanano, and H. Nogami. Pharmacokinetic aspects of elimination from plasma and distribution to brain and liver of barbiturates in rats.Chem. Pharm. Bull. 21:2749–2756 (1973).

    Article  CAS  PubMed  Google Scholar 

  10. T. Morishita, M. Yamazaki, N. Yata, and A. Kamada. Studies on absorption of drugs. VIII. Physicochemical factors affecting the absorption of sulfonamides from rat small intestine.Chem. Pharm. Bull. 21:2309–2322 (1973).

    Article  CAS  PubMed  Google Scholar 

  11. J. K. Seydel and K.-J. Schaper. Quantitative structure-pharmacokinetic relationships and drug design.Pharmacol. Ther. 15:131–182 (1982).

    Article  Google Scholar 

  12. W. A. Ritschel and G. V. Hammer. Prediction of the volume of distribution fromin vitro data and use for estimating the absolute extent of absorption.Int. J. Clin. Pharmacol. Ther. Toxicol. 18:298–316 (1980).

    CAS  PubMed  Google Scholar 

  13. J. K. Seydel. Quantitative structure-pharmacokinetic relationships and their importance in drug design, possibilities and limitations.Meth. Findings Exptl. Clin. Pharmacol. 6:571–581 (1984).

    CAS  Google Scholar 

  14. N. Kaneniwa, M. Hiura, and S. Nakagawa. Effect of lipid solubility and dose on the elimination of barbiturates in rabbits.Chem. Pharm. Bull. 27:1501–1509 (1979).

    Article  CAS  PubMed  Google Scholar 

  15. K. Kakemi, T. Arita, R. Hori, and R. Konishi. Absorption and excretion of drugs. XXX. Absorption of barbituric acid derivatives from rat stomach.Chem. Pharm. Bull. 15:1534–1539 (1967).

    Article  CAS  PubMed  Google Scholar 

  16. M. Hiura, S. Nakagawa, H. Kawashima, and N. Kaneniwa. Effect of lipid solubility on hepatic first-pass metabolism of barbiturates in rabbits.Int. J. Pharmaceut. 20:73–85 (1984).

    Article  CAS  Google Scholar 

  17. R. Kuntzman. Drugs and enzyme induction.Ann. Rev. Pharmacol. 9:21–36 (1969).

    Article  CAS  PubMed  Google Scholar 

  18. N. Kaneniwa, M. Hiura, and T. Funaki. Effect of fasting on the elimination of barbital and phenobarbital in rabbits.Chem. Pharm. Bull. 27:2157–2162 (1979).

    Article  CAS  PubMed  Google Scholar 

  19. M. Rowland, L. Z. Benet, and G. G. Graham. Clearance concepts in pharmacokinetics.J. Pharmacokin. Biopharm. 1:123–136 (1973).

    Article  CAS  Google Scholar 

  20. G. R. Wilkinson and D. G. Shand. A physiological approach to hepatic drug clearance.Clin. Pharmacol. Ther. 18:377–390 (1975).

    CAS  PubMed  Google Scholar 

  21. K. S. Pang and M. Rowland. Hepatic clearance of drugs. I. Theoretical considerations of a “well-stirred” model and a “parallel-tube” model. Influence of hepatic blood flow, plasma and blood cell binding, and the hepatocellular enzymatic activity on hepatic drug clearance.J. Pharmacokin. Biopharm. 5:625–653 (1977).

    Article  CAS  Google Scholar 

  22. L. Bass, S. Keiding, K. Winkler, and N. Tygstrup. Enzymatic elimination of substrates flowing through the intact liver.J. Theor. Biol. 61:393–409 (1976).

    Article  CAS  PubMed  Google Scholar 

  23. L. Bass and K. Winkler. A method of determining intrinsic hepatic clearance from the first-pass effect.Clin. Exp. Pharmacol. Physiol. 7:339–343 (1980).

    Article  CAS  PubMed  Google Scholar 

  24. J. G. Wagner, G. J. Szpunar, and J.J. Ferry. Exact mathematical equivalence of the venous equilibration (“well-stirred”) model, the sinusoidal perfusion (“parallel-tube”) model, and a specific two-compartment open model.Drug Metab. Dispos. 12:385–388 (1984).

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  26. M. Gibaldi, R. N. Boyes, and S. Feldman. Influence of first-pass effect on availability of drugs on oral administration.J. Pharm. Sci. 60:1338–1340 (1971).

    Article  CAS  PubMed  Google Scholar 

  27. J. G. Wagner. Comparison of nonlinear pharmacokinetic parameters estimated from sinusoidal perfusion and venous equilibrium models.Biopharm. Drug Dispos. 6:23–31 (1985).

    Article  CAS  PubMed  Google Scholar 

  28. W. L. Chiou. Mean hepatic transit time in the determination of mean absorption time.J. Pharm. Sci. 72:1365–1368 (1983).

    Article  CAS  PubMed  Google Scholar 

  29. L. S. Schanker. Absorption of drugs from the rat colon.J. Pharmacol. Exp. Ther. 126:283–290 (1959).

    CAS  PubMed  Google Scholar 

  30. K. Kakemi, T. Arita, R. Hori, R. Konishi, and K. Nishimura. Absorption and excretion of drugs. XXXIII. The correlation between the absorption of barbituric acid derviatives from the rat small intestine and their binding to the mucosa.Chem. Pharm. Bull. 17:248–254 (1969).

    Article  CAS  PubMed  Google Scholar 

  31. K. Yamaoka, T. Nakagawa, and T. Uno. Statistical moments in pharmacokinetics.J. Pharmacokin. Biopharm. 6:547–558 (1978).

    Article  CAS  Google Scholar 

  32. S. Riegelman and P. Collier. The application of statistical moment theory to the evaluation ofin vivo dissolution time and absorption time.J. Pharmacokin. Biopharm. 8:509–534 (1980).

    Article  CAS  Google Scholar 

  33. E. W. Maynert and H. B. Van Dyke. The metabolism of barbiturates.Pharmacol. Rev. 1:217–242 (1949).

    CAS  PubMed  Google Scholar 

  34. E. L. Dobson and H. B. Jones. The behavior of intravenously injected particulate matter; its rate of disappearance from the flow stream as a measure of liver blood flow.Acta Med. Scand. 144 (Suppl. 273):1–71 (1952).

    Google Scholar 

  35. J. M. Neutze, F. Wyler, and A. M. Rudolph. Use of radioactive microspheres to assess distribution of cardiac output in rabbits.Am. J. Physiol 215:486–495 (1968).

    CAS  PubMed  Google Scholar 

  36. L. E. Gaudette and B. B. Brodie. Relationship between the lipid solubility of drugs and their oxidation by liver microsomes.Biochem. Pharmacol. 2:89–96 (1959).

    Article  CAS  PubMed  Google Scholar 

  37. C. Hansch, A. R. Steward, S. M. Anderson, and D. Bentley. The parabolic dependence of drug action upon lipophilic character as revealed by a study of hypnotics.J. Med. Chem. 11:1–11 (1967).

    Article  Google Scholar 

  38. C. Hansch. Quantitative relationships between lipophilic character and drug metabolism.Drug. Metab. Rev. 1:1–14 (1972).

    Article  Google Scholar 

  39. T. D. Yih and J. M. van Rossum.Ks values of some homologous series of barbiturates and the relationship with the lipophilicity and metabolic clearance.Biochem. Pharmacol. 26:2117–2120 (1977).

    Article  CAS  PubMed  Google Scholar 

  40. I. Jansson, S. Orrenius, L. Ernster, and J. B. Schenkman. A study of the interaction of a series of substituted barbituric acids with the hepatic microsomal monooxygenase.Arch. Biochem. Biophys. 151:391–400 (1972).

    Article  CAS  PubMed  Google Scholar 

  41. J. C. Topham. Relationship between difference spectra and metabolism. Barbiturates, drug interaction, and species difference.Biochem. Pharmacol. 19:1695–1701 (1970).

    Article  CAS  PubMed  Google Scholar 

  42. M. Yamazaki, M. Aoki, and A. Kamada. Biological activity of drugs. IV. Physicochemical factors affecting the excretion of sulfonamides in rats.Chem. Pharm. Bull. 16:721–727 (1968).

    Article  CAS  PubMed  Google Scholar 

  43. T. Koizumi, T. Arita, and K. Kakemi. Absorption and excretion of drugs. XXI. Some pharmacokinetic aspects of absorption and excretion of sulfonamides (3). Excretion from the kidney.Chem. Pharm. Bull. 12:428–432 (1964).

    Article  CAS  PubMed  Google Scholar 

  44. Y. Sugiyama and M. Hanano. Pharmacokinetics. In Ito, Ohta, Nakashima, Nakamura, and Fukawa (eds.),Shin'yakuhinyoran-Rinshohen, R & D Planning, Tokyo, 1986, pp. 136–180.

    Google Scholar 

Download references

Author information

Author notes

  1. Mituru Hiura

    Present address: Takeshima Pharamceuticai Co. Ltd., Kasukabe, 344, Saitama-Prefecture, Japan

Authors and Affiliations

  1. School of Pharmaceutical Sciences, Showa University, Hatanodai, Shinagawa-ku, 142, Tokyo, Japan

    Nobutoshi Watari & Nobuyoshi Kaneniwa

  2. Faculty of Pharmaceutcial Sciences, University of Tokyo, Hongo, Bunkyo-ku, 113, Tokyo, Japan

    Yuichi Sugiyama

Authors
  1. Nobutoshi Watari
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yuichi Sugiyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nobuyoshi Kaneniwa
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mituru Hiura
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Watari, N., Sugiyama, Y., Kaneniwa, N. et al. Prediction of hepatic first-pass metabolism and plasma levels following intravenous and oral administration of barbiturates in the rabbit based on quantitative structure—Pharmacokinetic relationships. Journal of Pharmacokinetics and Biopharmaceutics 16, 279–301 (1988). https://doi.org/10.1007/BF01062138

Download citation

  • Received:

  • Revised:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01062138

Key words

Search

Navigation