Molecular Mechanisms of Drug Action and Pharmacokinetic-Pharmacodynamic Models

  • Wolfgang Sadée
Part of the Experimental Biology and Medicine book series (EBAM, volume 7)

Abstract

Drug response triggered by receptor activation arises from a chain of events that are regulated by many factors. Molecular changes associated with drug sensitization or tolerance are currently being elucidated on the molecular level, e.g. for adenylate cyclase coupled systems. Despite the complexity of the drug-response mechanism, simple empirical pharmaco-dynamic models on the basis of the law of mass action are widely applicable to describe drug-effect relationships. In combination with a pharmacokinetic model and suitable delay functions, such models are capable of simulating the complete time course of drug action in vivo. The predictive potential of the pharmacokinetic-pharmacodynamic models should prove useful in evaluating pharmaceutical formulations with controlled drug delivery.

Keywords

Morphine Warfarin Digoxin Neuroblastoma Cimetidine 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Ariens, E.J. and Simonis, A.M., A molecular basis of drug action. J. Pharm. Pharmacol., 16 (1964a) 137–157.CrossRefGoogle Scholar
  2. Ariens, E.J. and Simonis, A.M., A molecular basis for drug action. The interaction of one or more drugs with different receptors. J. Pharm. Pharmacol., 16 (1964b), 289–312.CrossRefGoogle Scholar
  3. Ariens, E.J., van Rossum, J.M. and Koopman, P.C., Receptor reserve and threshold phenomena. I. Theory and experiments with autonomic drugs tested on isolated organs. Arch. Int. Pharmacodyn. 127 (1960) 459–478.PubMedGoogle Scholar
  4. Asano, T., Katada, T., Gilman, A.G. and Ross, E.M., Activation of the inhibitory GTP-binding protein of adenylate cyclase, Gi, by ß-adrenergic receptors in reconstituted phospholipid vesicles. J. Biol. Chem., 259 (1984) 9351–9354.PubMedGoogle Scholar
  5. Chavkin, C. and Goldstein, A., Reduction in opiate receptor reserve in morphine tolerant guinea pig ilea. Life Sci., 31 (1982) 1687–1690.PubMedCrossRefGoogle Scholar
  6. Colburn, W.A., Simultaneous pharmacokinetic and pharmacodynamic modeling. J. Pharmacokin. Biopharm., 9 (1981) 367–388.CrossRefGoogle Scholar
  7. Dahlstrom, B.E., Paalzow, L.K., Segre, G. and âgren, A.J., Relation between morphine pharmacokinetics and analgesia. J. Pharmacokin. Biopharm., 6 (1978) 41–53.CrossRefGoogle Scholar
  8. Farfel, Z.A., Brickman, A.S., Kaslow, H.R., Brothers, V.M. and Bourne, H.R., N. Engl. J. Med., 303 (1980) 237–242.PubMedCrossRefGoogle Scholar
  9. Gilman, A.G., Proteins and dual control of adenylate cyclase. Cell, 36 (1984) 577–579.PubMedCrossRefGoogle Scholar
  10. Hall, H. and Ogren, S.-O., Effects of antidepressant drugs on different receptors in the brain. Europ. J. Pharmacol., 70 (1981) 393–407.CrossRefGoogle Scholar
  11. Hill, A.V., The possible effects of the aggregation of the molecules of haemoglobin on its dissociation curves. J. Physiol. (Lond.), 40 (1910) iv-vii.Google Scholar
  12. Holford, N.H.G., Drug concentration, binding and effect in vivo. Pharm. Res., (1984) 102–105.Google Scholar
  13. Holford, N.H.G. and Sheiner, L.B., Kinetics of pharmacological response. Pharmac. Ther., 16 (1982) 143–166.Google Scholar
  14. Katada, T. and Ui, M., ADP ribosylation of the specific membrane protein of CG cells by islet activating protein associated with modification of adenylate cyclase activity. J. Biol. Chem., 257 (1982) 7210–7216.PubMedGoogle Scholar
  15. Kurowski, M, Rosenbaum, J.S, Perry, D.C. and Sadée, W., 3H-Etorphine and 3H-diprenorphine receptor binding in vitro and in vivo. Differential effects of Na+ and GPP(NH)P. Brain Res. 249 (1982) 345–352.PubMedCrossRefGoogle Scholar
  16. Krieger, D.T. Brain peptides. What, where, why? Science, 222 (1983) 975–985.PubMedCrossRefGoogle Scholar
  17. Law, P.Y., Hom, D.S. and Loh, H.H., Opiate receptor down-regulation and desensitization in neuroblastoma x glioma NG-108–15 hybrid cells are two separate cellular adaptation processes. Molec. Pharmacol., 24 (1983) 413–424.Google Scholar
  18. Law, P.-Y., Hom, D.S. and Loh, H.H., Down-regulation of opiate receptor in neuroblastoma x glioma NG 108–15 hybrid cells. J. Biol. Chem., 259 (1984) 4096–4104.PubMedGoogle Scholar
  19. Levy, G., Kinetics of pharmacological effect. Clin. Pharmacol. Ther., 7 (1966) 362–372.Google Scholar
  20. Menkes, D.B., Rasenick, M.M., Wheeler, M.A. and Bitensky, M.W., Guanosine triphosphate activation of brain adenylate cyclase: Enhancement by long-term antidepressant treatment. Science, 219 (1983) 65–67.PubMedCrossRefGoogle Scholar
  21. Paalzow, L.K. and Edlund, P.O., Multiple receptor responses: A new concept to describe the relationship between pharmacological effects and pharmacokinetics of a drug: Studies on clonidine in the rat and cat. J. Pharmacokin. Biopharm., 7 (1979) 495–510.CrossRefGoogle Scholar
  22. Perry, D.C., Mullis, K.B., Oie, S. and Sadée, W., Opiate antagonist receptor binding in vivo: Evidence for a new receptor binding model. Brain Res., 199 (1980) 46–61.CrossRefGoogle Scholar
  23. Perry, D.C., Rosenbaum, J.S., Kurowski, M. and Sadée W., [3H]Etorphine receptor binding in vivo: Small fractional occupancy elicits analgesia. Molec. Pharmacol., 21 (1982) 272–279.Google Scholar
  24. Rodbell, M., The role of hormone receptors and GTP regulatory proteins in membrane transduction. Nature, 284 (1980) 17–22.PubMedCrossRefGoogle Scholar
  25. Rosenbaum, J.S., Holford, N.H.G. and Sadée, W., Opiate receptor binding-effect relationship: Sufentanil and etorphine produce analgesia at the p-site with low fractional occupancy. Brain Res., 291 (1984a) 317–324.CrossRefGoogle Scholar
  26. Rosenbaum, J.S., Holford, N.H.G., Richards, M.L., Aman, R.A. and Sadée, W., Discrimination of three types of opiate binding sites in rat brain in vivo. Molec. Pharmacol., 25 (1984b) 242–248.Google Scholar
  27. Scheideler, M.A., Lockney, M.W. and Dawson, G., Cell cycle-dependent expression of specific opiate binding with variable coupling to adenylate cyclase in a neurotumor hybrid cell line NG 108–15. J. Neurochem., 41 (1983) 1261–1268.PubMedCrossRefGoogle Scholar
  28. Scheiner, L.B., Stanski, D.R., Vozeh, S., Miller, R.D. and Ham, J., Simultaneous modeling of pharmacokinetics and pharmacodynamics: Application to d-tubocurarine. Clin. Pharmacol. Ther. 25 (1979) 358–371.Google Scholar
  29. Snyder, S.H. and Goodman, R.R., Multiple neurotransmitter receptors. J. Neurochem., 35 (1980) 5–15.PubMedCrossRefGoogle Scholar
  30. Strickland, S. and Loeb, J.N. Obligatory separation of hormone binding and biological response curves in systems dependent upon secondary mediators of hormone action. Proc. Natl. Acad. Sci. USA, 78 (1981) 1366–1370.PubMedCrossRefGoogle Scholar
  31. Strulovici, B., Cerione, R.A., Kilpatrick, B.F., Caron, M.G. and Lefkowitz, R.J. Direct demonstration of impaired functionality of a purified desensitized ß-adrenergic receptor in a reconstituted system. Science, 225 (1984) 837–840.PubMedCrossRefGoogle Scholar
  32. Tempel, A., Gardner, E.L. and Zukin, R.S., Visualization of opiate receptor upregulation by light microscopy autoradiography. Proc. Natl. Acad. Sci. USA, 81 (1984) 3893–3897.PubMedCrossRefGoogle Scholar
  33. Wagner, J.G., Kinetics of pharmacological response. I. Proposed relationship between response and drug concentration in the intact animal and man. J. Theoret. Biol., 20 (1968) 173–201.Google Scholar
  34. Wagner, J.G., Aghajanian, G.K. and Bing, O.H.L., Correlation of performance test scores with “tissue concentration” of lysergic acid diethylamide in human subjects. Clin. Pharmacol. Ther., 9 (1968) 635–638.Google Scholar

Copyright information

© The Humana Press Inc. 1985

Authors and Affiliations

  • Wolfgang Sadée
    • 1
  1. 1.School of PharmacyUniversity of CaliforniaSan FranciscoUSA

Personalised recommendations