Skip to main content
SpringerLink
Log in

Quantitative relationships between structure and pharmacokinetics of beta-adrenoceptor blocking agents in man

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

An Erratum to this article was published on 01 December 1984

Abstract

The structure and pharmacokinetics relationship of 14-beta-adrenoceptor antagonists was investigated in humans. Statistically significant linear and parabolic correlations were found to exist between standard and derived mean pharmacokinetic parameters and the apparent octanol/buffer (pH7.4) partition coefficient of the compounds. The lipophilic/hydrophilic properties were the primary determinants for the pharmacokinetic behavior of the compounds. Most of the pharmacokinetic parameters were also significantly correlated with the plasma protein/plasma water partition coefficient for the compounds. When the values of the pharmacokinetic parameters of the individual compounds were predicted from the regressions on the apparent partition coefficients in octanol/buffer (pH 7.4) and in plasma protein/plasma water, the error was on average 60%.

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 and K. J. Schaper.Chemische Struktur und biolog. Aktivität von Wirkstoffen, Verlag Chemie, Weinheim, 1979, p. 73.

    Google Scholar 

  2. W. A. Craig and P. G. Welling. Protein binding of antimicrobials, clinical pharmacokinetics and therapeutic implications.Clin. Pharmacokin. 2:252–268 (1976).

    Article  Google Scholar 

  3. W. J. Jusko and M. Gretch. Plasma and tissue protein binding of drugs in pharmacokinetics.Drug. Metab. Rev. 5:43–140 (1976).

    Article  CAS  PubMed  Google Scholar 

  4. J. K. Seydel. In J. C. Dowden (ed.),Quantitative Approaches in Drug Design, Elsevier, Amsterdam, 1983.

    Google Scholar 

  5. J. K. Seydel, D. Trettin, O. Wassermann, and M. Maliusz. Quantitative Struktur-Pharmacokinetik-Beziehungen am Beispiel von Sulfonamidobenzolen und Sulfanilamidopyridinen.J. Med. Chem. 23:607–613 (1980).

    Article  CAS  PubMed  Google Scholar 

  6. J. K. Seydel and K.-J. Schaper. In M. Rowland and G. T. Tucker (eds.),Pharmacology and Therapeutics, Vol. 15, Pergamon Press, Elmsford, N.Y., 1982.

    Google Scholar 

  7. A. J. Smith and G. T. Tucker. Kinetics and biotransformation of adrenergic inhibitors. In L. Szekeres (ed.),Adrenergic Activators and Inhibitors, Handbook Exp. Pharmacol, Springer-Verlag, Berlin, 1980, pp. 417–509.

    Google Scholar 

  8. N. D. S. Bax, M. S. Lennard, S. Al-Asady, C. S. Deacon, G. T. Tucker, and H. F. Woods. Inhibition of drug metabolism by beta-adrenoceptor antagonists.Drugs 25:(Suppl. 2): 121–126 (1983).

    Article  CAS  Google Scholar 

  9. D. B. Jack. Is there a relationship between the physical properties and cardioselectivity of beta-adrenoceptor antagonists?Br. J. Clin. Pharmacol. 11:402–405 (1981).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. G. Neil-Dwyer, J. Artlett, J. McAinsh, and J. M. Cruishank. Beta-adrenoceptor blockers and the blood-brain barrier.Br. J. Clin. Pharmacol. 11:549–553 (1981).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. S. H. Unger and C. H. Chiong. Octanol-physiological buffer distribution coefficients of lipophilic amines by reversed-phase high performance liquid chromatography and their correlation.J. Med. Chem. 24:262–270 (1981).

    Article  CAS  PubMed  Google Scholar 

  12. P. B. M. W. M. Timmermans, A. Brands, and D. A. von Zwieten. Lipophilicity and brain disposition of clonidine and structurally related imidazolidines.Naunyn-Schmiedebergs Arch. Pharmacol. 300:217–226 (1977).

    Article  CAS  PubMed  Google Scholar 

  13. O. Fini, F. Brusa, and L. Chiesa. Bestimmung der Testzeit in der “Reversed-Phase” Hochdruckflüssigkeits-Chromatographie.J. Chromatogr. 210:326–330 (1981).

    Article  CAS  Google Scholar 

  14. A. C. Guyton.Testbook of Physiology, 4th ed., W. B. Saunders, Philadelphia, 1971, p. 427.

    Google Scholar 

  15. L. W. Schanker, P. A. Nafpliotis, and J. M. Johnson. Passage of organic bases into human red cells.J. Pharmacol. 133:325–331 (1961).

    CAS  Google Scholar 

  16. P. H. Hinderling. Kinetics of partitioning and binding of digoxin and analogs in the subcompartments of blood.J. Pharm. Sci., in press.

  17. B. D. Davis. The binding of sulfonamide drugs by plasma proteins. A factor in determining the distribution of drugs in the body.J. Clin. Invest. 22:753–762 (1943).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. M. Gibaldi and P. J. McNamara. Apparent volumes of distribution and drug binding to plasma proteins and tissues.Eur. J. Clin. Pharmacol. 13:373–378 (1978).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  20. J. P. Kampman and J. Mølholm-Hansen. Glornerular filtration rate and creatinine clearance.Br. J. Clin. Pharmacol. 12:7–14 (1981).

    Article  Google Scholar 

  21. P. Hajdu and P. Damm. Physico-chemical and analytical studies of penbutolol.Arzneim. Forsch. 29:602–606 (1979).

    CAS  Google Scholar 

  22. M. Eckert, Hoffmann-La Roche Inc., Basle, Switzerland, personal communication.

  23. D. A. Stopher, Pfizer Ltd., Sandwich, England, personal communication.

  24. D. C. Hicks. The buccal absorption of some beta-adrenoceptor blocking drugs.Br. J. Pharmacol. 47:680P-681P (1973).

    CAS  PubMed Central  PubMed  Google Scholar 

  25. N. O. Bodin, K. O. Borg, R. Johannson, H. Obianwu, and R. Svenson. Absorption, distribution and excretion of alprenolol in man, dog and rat.Acta Pharmacol. Toxicol. 35:261–269 (197).

  26. C. P. Dawes, M. J. Kendall, and V. A. John. Comparison of plasma and saliva levels of metoprolol and oxprenolol.Br. J. Pharmacol. 5:217–221 (1978).

    Article  CAS  Google Scholar 

  27. R. Tempelton, May Baker Ltd., Dagenham, England, personal communication.

  28. P. Vermeij. Kinetische aspecten van einige beta-blockkeerbers, Ph.D. thesis, Amsterdam, 1976.

  29. C.-G. Regårdh, K. O. Borg, R. Johansson, G. Johnsson, and L. Palmer. Pharmacokinetic studies on the selective beta,-receptor antagonist metoprolol in man.J. Pharmacokin. Biopharm. 2:347–364 (1974).

    Article  Google Scholar 

  30. M. Lemaire and J. P. Tillement. The binding characteristics of some adrenergic betareceptor antagonists to human serum proteins.Biochem. Pharmacol. 31:359–362 (1982).

    Article  CAS  PubMed  Google Scholar 

  31. H. K. Adam, Imperial Chemical Industries Ltd., Macclesfield, England, personal communication.

  32. U. N. Pfluger, Squibb Inc., Zürich, Switzerland, personal communication.

  33. E. R. Garrett and K. Schnelle. Separation and spectrofluorometric assay of the betaadrenergic blocker sotalol from blood and urine.J. Pharm. Sci. 60:833–839 (1971).

    Article  CAS  PubMed  Google Scholar 

  34. D. Hellenbrecht, B. Lemmer, G. Wiethold, and H. Grobecker. Measurement of hydrophobicity, surface activity, local anesthesia and myocardial conduction velocity as quantitative parameters of the non-specific membrane affinity of nine beta-adrenergic blocking agents.Naunyn-Schmiedebergs Arch. Pharmacol. 277:211–226 (1973).

    Article  CAS  PubMed  Google Scholar 

  35. T. J. Coombs and C. J. Coulson, May Baker Ltd., Dagenham, England, personal communication.

  36. W. Riess, S. Brechbühler, and W. Theobald. The pharmacokinetic characteristics of beta-receptor antagonists in man-similarities and differences of clinical relevance.Aust. N. Z. J. Med. 6(Suppl.3):4–13 (1976).

    Article  Google Scholar 

  37. T. J. Coombs, C. J. Coulsen, and V. J. Smith. Blood plasma binding of acebutolol and diacetolol in man.Br. J. Clin. Pharmacol. 9:395–397 (1980).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. C. Appelgreen, K. O. Borg, R. Elofsson, and K. A. Johannson. Binding of adrenergic beta-receptor-antagonists to human serum albumin.Acta Pharm. Suec. 11:325–332 (1974).

    Google Scholar 

  39. P. B. Woods and H. L. Robinson. An investigation of the comparative liposolubilities of beta-adrenoceptor blocking agents. JPharm. Pharmacol. 33:172–173 (1981).

    Article  CAS  PubMed  Google Scholar 

  40. J. K. Faulkner, D. A. Stopher, R. Waiden, W. Singleton, and S. H. Taylor. Pharmacokinetic and pharmacological studies with tolamolol in man.Br. J. Clin. Pharmacol. 2:423–428 (1975).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. F. M. Belpaire, M. G. Bogaert, and M. Rosseneu. Binding of beta-adrenoceptor blocking drugs to human serum albumin, to alpha1-glycoprotein and to human serum.Eur. J. Clin. Pharmacol. 22:253–256 (1982).

    Article  CAS  PubMed  Google Scholar 

  42. P. J. Meffin, R. A. Winkle, F. A. Peters, and D. C. Harrison. Acebutolol disposition after intravenous administration.Clin. Pharmacol. Ther. 22:557–567 (1977).

    CAS  PubMed  Google Scholar 

  43. J. A. Henry and S. N. Mitchell. Effect ofpH on human plasma protein binding of a series of beta-adrenoceptor antagonists.Br. J. Clin. Pharmacol. 11:119P-120P (1980).

    Google Scholar 

  44. J. Dreyfuss, J. Brannick, R. A. Yukovich, J. M. Shaw, and D. A. Willard. Metabolic studies in patients with nadolol: oral and intravenous administration.J. Clin. Pharmacol. 17:300–307 (1977).

    Article  CAS  PubMed  Google Scholar 

  45. M. Antilla, M. Arstila, M. Pfeffer, R. Tikkanen, V. Vallinkoski, and H. Sundquist. Human pharmacokinetics of sotalol.Acta Pharmacol. Toxicol. 39:118–128 (1976).

    Article  Google Scholar 

  46. L. B. Jellet and D. G. Shand. Uptake of propranolol by washed human red cells.Pharmacologist 15:215 (1973).

    Google Scholar 

  47. G. Alvan, K. Piafsky, M. Lind, and C. von Bahr. Effect of pentobarbital on the disposition of alprenolol.Clin. Pharmacool Ther. 22:316–321 (1977).

    CAS  Google Scholar 

  48. J. P. Dubois, CIBA-GEIGY Ltd., Basle, Switzerland, personal communication.

  49. M. Lemaire, Ph.D. thesis, Universite de Paris de l'Est, 1982.

  50. P. R. Reeves, D. E. Case, H. T. Jepson, D. J. McCormick, J. T. Nickolls, R. H. Felix, P. J. Holt, K. J. Zacharias, and R. W. Fluke. Practolol metabolism II. Metabolism in human subjects.J. Pharmacol. Exp. Ther. 205:489–498 (1978).

    CAS  PubMed  Google Scholar 

  51. E. A. Taylor and P. Turner. The distribution of propranolol, pindolol and atenolol between human erythrocytes and plasma.

  52. D. G. Shand, Durham, N.C., personal communication.

  53. G. Alvan, M. Lind, B. Mellström, and C. Bahr. Importance of first pass elimination for interindividual differences in steady-state concentrations of the adrenergic beta-receptor antagonist alprenolol.J. Pharmacokin. Biopharm. 5:193–205 (1977).

    Article  CAS  Google Scholar 

  54. G. Alvan, Huddinge, Sweden, personal communication.

  55. D. Vermeij, M. El Sherbini-Schepers, and P. A. van Zwieten. The disposition of timolol in man.J. Pharm. Pharmacol. 30:53–55 (1978).

    Article  CAS  PubMed  Google Scholar 

  56. D. Vermeij, Amsterdam, The Netherlands, personal communication.

  57. L. Jördo, P. O. Attman, M. Aurell, L. Johannson, G. Johanson, and C.-G. Regårdh. Pharmacokinetic and pharmacodynamic properties of metoprolol in patients with impaired renal function.Clin. Pharmacokin. 5:169–180 (1980).

    Article  Google Scholar 

  58. N. Ph. Chau, Y. A. Weiss, M. E. Safar, D. E. Lavene, D. R. Georges, and P. L. Milliez. Pindolol availability in hypertensive patients with normal and impaired renal function.Clin. Pharmacol. Ther. 22:505–510 (1977).

    CAS  PubMed  Google Scholar 

  59. W. D. Mason, N. Winer, G. Kochak, I. Cohen, and R. Bell. Kinetics and absolute bioavailability of atenolol.Clin. Pharmacol. Ther. 25:408–415 (1979).

    CAS  PubMed  Google Scholar 

  60. L. Balant, R. J. Francis, T. N. Tozer, A. Marmy, J.-M. Tschopp, and J. Fabre. Influence of renal failure on the hepatic clearance of bufuralol in man.J. Pharmacokin. Biopharm. 8:421–438 (1980).

    Article  CAS  Google Scholar 

  61. T. Walle, E. C. Conradi, U. K. Walle, T. C. Fagan, and T. E. Gaflney. The predictable relationship between plasma levels and dose during chronic propranolol therapy.Clin. Pharmacol. Ther. 24:668–677 (1978).

    CAS  PubMed  Google Scholar 

  62. C.-G. Regårdh. Pharmacokinetics and biopharmaceutics of some adrenergic beta-receptor antagonists with special emphasis on alprenolol and metoprolol.Acta Pharmacol. Toxicol. (Kbh) 37(Suppl. 1):1–39 (1975).

    Google Scholar 

  63. M. J. Kendall, M. Mitchard, M. West, V. A. John, and A. F. Ebbutt. Factors influencing the absorption of oxprenolol, a pharmacokinetic study.Eur. J. Drug. Metab. Pharmacokin. 1:155–160 (1976).

    Article  CAS  Google Scholar 

  64. D. T. Lowenthal, M. Sorenson, and I. R. Edwards. Timolol kinetics in chronic renal insufficiency.Clin. Pharmacol. Ther. 23:606–615 (1978).

    CAS  PubMed  Google Scholar 

  65. G. Johannson, C.-G. Regårdh, and L. Sölvell. Lack of biological interaction of alprenolol and salicylate in man.Eur. J. Clin. Pharmacol. 6:9–14 (1973).

    Article  Google Scholar 

  66. H. W. Smith.The Kidney: Structure and Function in Health and Disease. Oxford University Press, New York, 1951.

    Google Scholar 

  67. L. Balant, K. Muir, P. Dayer, A. Georgia, J. L. Eberlin, J. Estreicher, and J. Fabre. Simultaneous tubular excretion and reabsorption of pindolol in man.Eur. J. Clin. Pharmacol. 21:65–72 (1981).

    Article  CAS  PubMed  Google Scholar 

  68. R. Gomeni, G. Bianchetti, R. Sega, and P. L. Morselli. Pharmacokinetics of propranolol in normal healthy volunteers.Clin. Pharmacol. Ther. 20:401–412 (1978).

    Google Scholar 

  69. O. F. Else, H. Sörenson, and I. R. Edwards. Plasma timolol levels after oral and intravenous administration.Eur. J. Clin. Pharmacol. 14:431–434 (1978).

    Article  CAS  PubMed  Google Scholar 

  70. W. D. Mason and N. Winer. Pharmacokinetics of oxprenolol in normal subjects.Clin. Pharmacol. Ther. 20:401–412 (1976).

    CAS  PubMed  Google Scholar 

  71. H. Boxenbaum. Comparative pharmacokinetics of benzodiazepines in dog and man.J. Pharmacokin. Biopharm. 10:411–426 (1982).

    Article  CAS  Google Scholar 

Download references

Author information

Author notes

  1. Olga Schmidlin

    Present address: Department of Internal Medicine, University of Basle, Petersgraben 6, 4059, Basle, Switzerland

Authors and Affiliations

  1. Department of Pharmacology, Biocenter, University of Basle, Klingelbergstr. 70, 4056, Basle, Switzerland

    Peter H. Hinderling & Olga Schmidlin

  2. Department of Medicinal and Pharmaceutical Chemistry, Research Institute of Borstel, Parkallee 1-40, 2061, Borstel, Federal Republic of Germany

    Jochen K. Seydel

Authors
  1. Peter H. Hinderling
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Olga Schmidlin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jochen K. Seydel
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

An erratum to this article is available at http://dx.doi.org/10.1007/BF01059560.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hinderling, P.H., Schmidlin, O. & Seydel, J.K. Quantitative relationships between structure and pharmacokinetics of beta-adrenoceptor blocking agents in man. Journal of Pharmacokinetics and Biopharmaceutics 12, 263–287 (1984). https://doi.org/10.1007/BF01061721

Download citation

  • Received:

  • Revised:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01061721

Key words

Search

Navigation