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Journal of Pharmacokinetics and Biopharmaceutics

, Volume 6, Issue 6, pp 559–585 | Cite as

Effect of route of administration and distribution on drug action

  • Leslie Z. Benet
Scientific Commentary

Abstract

The extent and time course of drug action can be markedly affected by the route of drug administration into the patient as well as the pattern of drug distribution within the patient. Drugs which are rapidly cleared by hepatic processes will show a decreased extent of availability following oral administration due to metabolism of drug on its first pass through the liver. The magnitude of this first pass will depend on the blood flow to the liver and the intrinsic clearing ability of the liver (i.e., the ability of the organ to eliminate the drug independent of the rate at which drug is brought to the organ). Drug distribution in the patient will depend on the blood flow to various sites in the body as well as the partition coefficient of the drug between the blood and the distributive organs. Protein binding both in the plasma and in the tissues will markedly affect this distribution. However, free drug concentrations are generally believed to be the effective determinant in drug therapy. Often a redistribution due to changes in protein binding will have little effect on the therapeutic efficacy since, although total drug distribution changes, free concentrations in the plasma remain essentially similar.

Key words

first-pass effect clearance route of administration drug distribution volume of distribution protein binding 

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References

  1. 1.
    L. Z. Benet. Biopharmaceutics as a basis for the design of drug products. In E. Ariens (ed.),Drug Design, Vol. IV, Academic Press, New York, 1973, pp. 1–35.CrossRefGoogle Scholar
  2. 2.
    L. Z. Benet. Input factors as determinants of drug activity: Route, dose, dosage regimen, and the drug delivery system. In F. Gilbert McMahon (ed.),Principles and Techniques of Human Research and Therapeutics, Vol. III, Futura Publishing Co., New York, 1974, pp. 9–23.Google Scholar
  3. 3.
    J. J. Sciarra. Aerosols. In Joseph B. Sprowls, Jr. (ed.),Prescription Pharmacy, 2nd ed., Lippincott, Philadelphia, 1970, pp. 280–328.Google Scholar
  4. 4.
    F. W. Lovejoy, Jr., H. Constantine, and L. Dautrebande. Importance of particle size in aerosol therapy.Proc. Soc. Exp. Biol. Med. 103:836–838 (1960).PubMedCrossRefGoogle Scholar
  5. 5.
    J. R. Vane. The role of the lungs in the metabolism of vasoactive substances. In T. Teorell, R. L. Dedrick, and P. G. Condliffe (eds.),Pharmacology and Pharmacokinetics, Plenum Press, New York, 1974, pp. 195–207.Google Scholar
  6. 6.
    M. Rowland. Influence of route of administration on drug availability.J. Pharm. Sci. 61:70–74 (1972).PubMedCrossRefGoogle Scholar
  7. 7.
    M. Rowland. Effect of some physiologic factors on bioavailability of oral dosage forms. In J. Swarbrick (ed.),Dosage Form Design and Bioavailability, Lea and Febiger, Philadelphia, 1973, pp. 181–222.Google Scholar
  8. 8.
    M. Rowland, L. Z. Benet, and G. G. Graham. Clearance concepts in pharmacokinetics.J. Pharmacokin. Biopharm. 1:123–136 (1973).CrossRefGoogle Scholar
  9. 9.
    E. F. Evans, J. D. Proctor, M. J. Fratkin, J. Velandia, and A. J. Wasserman. Blood flow in muscle groups and drug absorption.Clin. Pharmacol. Ther. 17:44–47 (1975).PubMedGoogle Scholar
  10. 10.
    L. S. Cohen, J. E. Rosenthal, D. W. Horner, Jr., J. M. Atkins, O. A. Matthews, and S. F. Sarnoff. Plasma levels of lidocaine after intramuscular administration.Am. J Cardiol. 29:520–523 (1972).PubMedCrossRefGoogle Scholar
  11. 11.
    M. L. Schwartz, M. B. Meyer, B. G. Covino, R. M. Narange, V. Sethi, A. J. Schwartz, and P. Kamp. Antiarrhythmic effectiveness of intramuscular lidocaine; influence of different injection sites.J. Clin. Pharmacol. 14:77–83 (1974).PubMedCrossRefGoogle Scholar
  12. 12.
    A. J. Wilensky and J. A. Lowden. Inadequate serum levels after intramuscular administration of diphenylhydantoin.Neurology 23:318–324 (1973).PubMedCrossRefGoogle Scholar
  13. 13.
    J. T. Doluisio, J. C. LaPiana, and L. W. Dittert. Pharmacokinetics of ampicillin trihydrate, sodium ampicillin, and sodium dicloxacillin following intramuscular injection.J. Pharm. Sci. 60:379–385 (1972).Google Scholar
  14. 14.
    M. Rowland, S. Riegelman, P. S. Harris, and S. D. Sholkoff. Absorption kinetics of aspirin in man following oral administration of an aqueous solution.J. Pharm. Sci. 61:379–385 (1972).PubMedCrossRefGoogle Scholar
  15. 15.
    J. F. Tait, B. Little, S. A. S. Tait, and C. Frood. The metabolic clearance rate of aldosterone in pregnant and nonpregnant subjects estimated by both single-injection and constantinfusion methods.J. Clin. Invest. 41:2093–2100 (1962).PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    J. Bougas, C. Frood, B. Little, J. F. Tait, S. A. S. Tait, and R. Underwood. In E. E. Baulieu and P. Probel (eds.),Symposium on Aldosterone, Blackwell Scientific Publications, Oxford, 1964, p. 25.Google Scholar
  17. 17.
    B. Ablad and G. Johnsson. Pharmacological effects and serum levels of orally administered alprenolol in man. InAbstracts of the Fifth International Congress on Pharmacology, July 23–28, 1972, San Francisco, p. 76.Google Scholar
  18. 18.
    C. T. Dollery, D. S. Davies, and M. E. Conolly. Differences in the metabolism of drugs depending upon their routes of administration.Ann. N. Y. Acad. Sci. 179:108–114 (1971).PubMedCrossRefGoogle Scholar
  19. 19.
    R. N. Boyes, D. B. Scott, P. J. Jepson, M. J. Goodman,and D.G. Julian. Pharmacokinetics of lidocaine in man.Clin. Pharmacol. Ther. 12:105–116 (1971).PubMedGoogle Scholar
  20. 20.
    P. D. Thomson, K. L. Melmon, J. A. Richardson, K. Cohn, W. Steinbrunn, R. Cudihee, and M. Rowland. Lidocaine pharmacokinetics in advanced heart failure, liver disease, and renal failure in humans.Ann. Intern. Med. 78:499–508 (1973).PubMedCrossRefGoogle Scholar
  21. 21.
    S. F. Brunk and M. Delle. Morphine metabolism in man.Clin. Pharmacol. Ther. 16:51–57 (1973).Google Scholar
  22. 22.
    A. H. Beckett, J. F. Taylor, and P. Kourounakis. The absorption, distribution and excretion of pentazocine in man after oral and intravenous administration.J. Pharm. Pharmacol. 22:123–128 (1970).PubMedCrossRefGoogle Scholar
  23. 23.
    A. H. Beckett, P. Kourounakis, D. P. Vaughan, and M. Mitchard. The absorption, blood concentrations and excretion of pentazocine after oral, intramuscular or rectal administration.J. Pharm. Pharmacol. 22:169S-174S (1970).CrossRefGoogle Scholar
  24. 24.
    R. L. Wolen, C. M. Gruber, G. F. Kiplinger, and N. E. Scholz. Concentration of propoxyphene in human plasma following oral, intramuscular, and intravenous administration.Toxicol. Appl. Pharmacol. 19:480–492 (1971).PubMedCrossRefGoogle Scholar
  25. 25.
    J. G. Wagner, P. G. Welling, S. B. Roth, E. Sakmar, K. P. Lee, and J. E. Walker. Plasma concentrations of propoxyphene in man. I. Following oral administration of the drug in solution and capsule forms.Int. J. Clin. Pharmacol. 5:371–380 (1972).Google Scholar
  26. 26.
    R. E. McMahon, A. S. Ridolfo, H. W. Culp, R. L. Wolen, and W. F. Marshall. The fate of radiocarbon-labeled propoxyphene in rat, dog, and human.Toxicol. Appl. Pharmacol. 19:427–444 (1971).PubMedCrossRefGoogle Scholar
  27. 27.
    J. W. Paterson, M. E. Conolly, C. T. Dollery, A. Hayes, and R. G. Cooper. The pharmacodynamics and metabolism of propranolol in man.Pharmacol. Clin. 2:127–133 (1970).CrossRefGoogle Scholar
  28. 28.
    D. G. Shand and R. E. Rangno. The disposition of propranolol. I. Elimination during oral absorption in man.Pharmacology 7:159–168 (1972).PubMedCrossRefGoogle Scholar
  29. 29.
    W. H. Barr and S. Riegelman. Effect of capacity limited metabolism on plasma levels of free salicylamide in man. InAbstracts of the 115th Annual Meeting of the American Pharmaceutical Association Academy of Pharmaceutical Sciences, Miami Beach, May 5–10, Washington, D.C., 1968, p. 58.Google Scholar
  30. 30.
    G. Levy and T. Matsuzawa. Pharmacokinetics of salicylamide elimination in man.J. Pharmacol. Exp. Ther. 156:285–293 (1967).PubMedGoogle Scholar
  31. 31.
    R. N. Boyes, J. H. Adams, and B. R. Duce. Oral absorption and disposition kinetics of lidocaine hydrochloride in dogs.J. Pharmacol. Exp. Ther. 174:1–8 (1970).PubMedGoogle Scholar
  32. 32.
    D. G. Shand, E. M. Nuckolls, and J. A. Oates. Plasma propranolol levels in adults with observations in four children.Clin. Pharmacol. Ther. 11:112–120 (1970).PubMedGoogle Scholar
  33. 33.
    W. H. Barr. Factors involved in the assessment of systemic or biologic availability of drug products.Drug Inform. Bull. 3:27–45 (1969).Google Scholar
  34. 34.
    M. Drucker, S. H. Blondheim, and L. Wislicki. Factors affecting acetylationin vivo of para-aminobenzoic acid by human subjects.Clin. Sci. 27:133–141 (1964).PubMedGoogle Scholar
  35. 35.
    E. M. Johnson, A. B. Harkey, D. J. Blehm, and P. Needleham. Metabolism and clearance of organic nitrates.Pharmacologist 13:268 (1971).Google Scholar
  36. 36.
    T. W. Schwarz. Molded solid dosage forms: Suppositories. In J. B. Sprowls, Jr., and H. M. Beal (eds.),American Pharmacy, 6th ed., Lippincott, Philadelphia, 1966, pp. 311–331.Google Scholar
  37. 37.
    R. L. Dedrick and K. B. Bischoff, Pharmacokinetics in applications of the artificial kidney.Chem. Eng. Prog. Symp. Ser. 64:32–44 (1968).Google Scholar
  38. 38.
    W. W. Mapleson. An electric analogue for uptake and exchange of inert gases and other agents.J. Appl. Physiol. 18:197–204 (1963).PubMedGoogle Scholar
  39. 39.
    K. B. Bischoff and R. L. Dedrick. Thiopental pharmacokinetics.J. Pharm. Sci. 57:1347–1357 (1968).CrossRefGoogle Scholar
  40. 40.
    J. G. Wagner.Fundamentals of Clinical Pharmacokinetics, Drug Intelligence Publications, Hamilton, Ill., 1975, pp. 24–26.Google Scholar
  41. 41.
    W. J. Jusko. Pharmacokinetics in disease states changing protein binding. In L. Z. Benet (ed.),The Effect of Disease States on Drug Pharmacokinetics, American Pharmaceutical Association, Academy of Pharmaceutical Sciences, Washington, D.C., 1976, pp. 99–123.Google Scholar
  42. 42.
    G. R. Wilkinson and D. G. Shand. A physiologic approach to hepatic drug clearance.Clin. Pharmacol. Ther. 18:377–390 (1975).PubMedGoogle Scholar
  43. 43.
    G. Levy. Clinical implications of interindividual differences in plasma protein binding of drugs and endogenous substances. In L. Z. Benet (ed.),The Effect of Disease States on Drug Pharmacokinetics, Academy of Pharmaceutical Sciences, American Pharmaceutical Association, Washington, D.C., 1976, pp. 137–151.Google Scholar

Copyright information

© Plenum Publishing Corporation 1978

Authors and Affiliations

  • Leslie Z. Benet
    • 1
  1. 1.Department of Pharmacy, School of PharmacyUniversity of CaliforniaSan Francisco

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