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Kinetics of combined drug action

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Abstract

For the purpose of obtaining quantitative concentration-effect relationship for combined drugs, rationales of the Hill equation were inferred and five models, i.e., normal distribution (NRD), derivative of R (DRV), vacancy-dependent binding (VDB), equiresponse (EQR), and independence (IND), were proposed to estimate the intensity of the combined drug action. In conclusion, we could not come up to the unique concentration-effect relationship. Among the five models, the EQR, NRD, and VDB models gave almost identical response intensity. Discrimination of these three models is not of great importance. The DRV model gave a characteristic concave isobologram (overadditive), for a given ratio of Hill constants and independent of pharmacologic effect. In contrast, the IND model was able to cope with convex isobolograms (underadditive).

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References

  1. G. Levy. An orientation to clinical pharmacokinetics. In Levy, G. (ed.),Clinical Pharmacokinetics: A Symposium, American Pharmaceutical Association, 1974, pp. 1–9.

  2. T. Koizumi and J. Zhu. An interpretation of the Hill equation: Time course of diuretic response after furosemide administration in man.J. Pharmacobiodyn. 14:113–119 (1991).

    Article  CAS  PubMed  Google Scholar 

  3. S. Lowe and H. Muischnek. Uber Kombinationswirkungen. I: Hilfsmittel der Fragestel-lung.Naunyn-Schmiedebergs Arch. Pharmakol. 114:313–326 (1926).

    Article  Google Scholar 

  4. G. Poch, R. J. Reifenstein, and H.-D. Unkelbach. Application of the isobologram technique for the analysis of combined effects with respect to additivity as well as independence.Can. J. Physiol Pharmacol. 68:682–688 (1990).

    Article  CAS  PubMed  Google Scholar 

  5. C. I. Bliss. The toxicity of poisons applied singly.Ann. Appl. Biol. 26:585–615 (1939).

    Article  CAS  Google Scholar 

  6. S. Narumi and T. Sakai.Suritokeigaku Yosetsu, Baifukan, Tokyo, 1967, p. 122.

    Google Scholar 

  7. M. Berman, E. Shahn, and M. F. Weiss. Routine fitting of kinetic data to model-formalism for digital computers.Biophys. J. 2:275–287 (1962).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. M. Mori.Kyokusen to Kyokumen, Kyoiku Shuppan, Tokyo, 1974, pp. 131–144.

    Google Scholar 

  9. A. G. Marshall, I. Kissin, J. G. Reves, E. L. Bradley, Jr., and E. H. Blackston. Interaction between negative inotropic effects of halothane and nifedipine in the isolated rat heart,J. Cardiovasc. Pharmacol 5:592–597 (1983).

    Article  CAS  PubMed  Google Scholar 

  10. K. Yamaoka, T. Nakagawa, and T. Uno. Application of Akaike's information criterion (AIC) in the evaluation of linear pharmacokinetic equation.J. Pharmacokin. Biopharm. 6:165–175 (1978).

    Article  CAS  Google Scholar 

  11. T. Hatanaka, S. Negishi, K. Katayama, M. Kakemi, and T. Koizumi. The pharmacodynamic and pharmacokinetic interaction of pentobarbital and chlorpromazine in rats.J. Pharmacobiodyn. 11:47–52 (1988).

    Article  CAS  PubMed  Google Scholar 

  12. W. Y. Hu, R. J. Reiffenstein, and L. Wong. Interaction between flurazepam and ethanol.Alcohol Drug Res. 7:107–117 (1986).

    Google Scholar 

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Koizumi, T., Kakemi, M. & Katayama, K. Kinetics of combined drug action. Journal of Pharmacokinetics and Biopharmaceutics 21, 593–607 (1993). https://doi.org/10.1007/BF01059116

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