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Evaluation of dose-related pharmacokinetics and pharmacodynamics of prednisolone in man

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Abstract

The pharmacokinetics and pharmacodynamics of prednisolone were evaluated in normal male volunteers. Seven subjects completed 3 phases: 16.4−and 49.2−mg iv prednisolone, and a phase with no drug to assess baseline responses. Plasma concentrations of prednisolone and urine concentrations of prednisolone and 5 metabolites were assayed by HPLC. Protein binding of prednisolone was measured by ultrafiltration. The polyexponential disposition of free and total plasma prednisolone were evaluated and apparent parameters were compared between doses. Suppression of plasma cortisol and alterations in blood basophil and helper-T cell trafficking were used as pharmacodynamic indices. Pharmacodynamic models were used to relate total or free plasma prednisolone concentrations to each of these effects generating response parameters and IC50 (50% inhibitory) concentrations common to both doses. The pharmacokinetics of total drug were comparable to previous findings with CLand Vss increasing with dose. Free prednisolone exhibited slight capacitylimited elimination and distribution as CLand Vss decreased with the larger dose. Pharmacodynamic models jointly fitting all three phases characterized the suppression/trafficking phenomena equally well with use of total or free drug concentrations. In each case the models provided realistic values of parameters relating to steroid sensitivity-in particular IC50-and to the underlying physiology of the affected systems. This study comprehensively elucidates the complexities of prednisolone pharmacokinetics and demonstrates how plasma concentration-time profiles of total or free prednisolone can be utilized for evaluation of prednisolone pharmacodynamics.

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Authors and Affiliations

  1. Departments of Pharmaceutics, Pharmacy, and Medicine, Schools of Pharmacy and Medicine, State University of New York at Buffalo, New York

    Jeffrey A. Wald, Rebecca M. Law, Elizabeth A. Ludwig, Rita R. Sloan, Elliott Middleton Jr. & William J. Jusko

  2. Departments of Pharmacy and Medicine, Buffalo General Hospital, Buffalo, New York

    Rebecca M. Law, Elizabeth A. Ludwig & Rita R. Sloan

Authors
  1. Jeffrey A. Wald
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  2. Rebecca M. Law
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  3. Elizabeth A. Ludwig
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  4. Rita R. Sloan
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  5. Elliott Middleton Jr.
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  6. William J. Jusko
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Additional information

Supported in part by Grants 24211 and 150-1885-0 from the National Institute of General Medical Sciences, National Institutes of Health. Presented in part at The American Society for Clinical Pharmacology and Therapeutics meeting, San Antonio, Texas. (Abstract:Clin. Pharmacol. Ther,49:179, 1991).

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Wald, J.A., Law, R.M., Ludwig, E.A. et al. Evaluation of dose-related pharmacokinetics and pharmacodynamics of prednisolone in man. Journal of Pharmacokinetics and Biopharmaceutics 20, 567–589 (1992). https://doi.org/10.1007/BF01064420

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