Successful application of information on cytochrome P450 to prevent drug interactions and improve the therapeutic risk: benefit ratio can occur only if we know which enzyme is responsible for the metabolism of a drug. Until recently, this information was not usually available when new drugs reached the market. It is not enough to know the fraction of a dose metabolized versus excreted unchanged or the metabolic pathways by which a compound is degraded. Studies conducted during drug development must identify the enzyme or enzymes involved in the metabolism of new drugs. In addition, the ability of new drugs to inhibit or induce the activity of the key P450 enzymes must be known if we are to take full advantage of our current knowledge of how the cytochrome P450 system works.

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It is known that loss of renal function decreases the hepatic clearance of some drugs, but the mechanisms by which this occurs are unclear. Knowledge of which drugs display reduced hepatic metabolism may be important for appropriate dosing of these drugs in uremic patients. Although no firm conclusions can be made regarding common pharmacokinetic and metabolic characteristics of drugs that display decreased hepatic metabolism in renal failure, certain observations deserve consideration. It appears that drugs metabolized by oxidation, conjugation, or both may be predisposed to decreased hepatic clearance in renal failure. Drugs that undergo oxidation by the P-450IID6 isozyme may be more likely to exhibit inhibition whereas those metabolized by the P-450IIIA4 isozyme may be spared. Future studies designed to clarify the mechanisms of decreased hepatic clearance in renal failure should take into account the multiplicity of P-450 enzymes for drugs that are oxidatively metabolized. The phenomenon of reduced hepatic drug clearance in uremia should be considered when evaluating the influence of renal failure on drug disposition.

Pharmacodynamic models for "directly suppressive" effects of methylprednisolone are based on the premise that receptor interactions of steroids are followed by immediate suppression of either the circadian secretion of cortisol or the constant rate recirculation of histamine-containing basophils that persists until inhibitory concentrations of methylprednisolone disappear. Methylprednisolone doses of 0, 10, 20, and 40 mg were given as the 21-succinate sodium salt in a balanced crossover study to six normal men. Plasma steroid concentrations and blood histamine were measured simultaneously. Both forms of methylnisolone exhibited linear kinetic parameters. One dynamic model quantitates the baseline circadian pattern and the decline and return of cortisol with similar parameter estimates for all three dose levels. A similar model describes the monoexponential decline and the log-linear return to steady-state baseline of blood histamine. Similar inhibitory concentration values for both effects approximated the equilibrium dissociation constant of in vitro steroid receptor binding. The new models are more physiologically appropriate for these steroid effects than three other models that are commonly employed in pharmacodynamics. Steroid effects generally appear to be receptor mediated with either nongene immediate responses or gene-mediated delayed effects. These models allow quantitation of the rapid effects of steroids with simple equations and common fitted parameters for all steroid dose levels.The diverse immunosuppressive and the antiinflammatory effects of glucocorticoids in human beings complicate the development of realistic and comprehensive kinetic and dynamic models for this class of agents. This is partly because of the complex mode of action of corticosteroids, which involves receptor binding and the formation of second messengers and proteins (which is mediated by deoxyribonucleic acid [DNA]). Such responses are typically characterized by a slow and delayed induction period. This receptorReprint requests: William J. Jusko, PhD, 565 Hochstetter Hall, School of Pharmacy, State University of New York at Buffalo, Buffalo, NY 14260. Presented in part at the Third Annual Meeting of American Association of Pharmaceutical Scientists (AAPS), Orlando, Florida, Oct. 30 to Nov. 3, 1988. NIH Public Access Author ManuscriptClin Pharmacol Ther. Author manuscript; available in PMC 2014 October 23. Published in final edited form as:Clin Pharmacol Ther. 1989 December ; 46(6): 616-628. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript gene mode of action has been successfully modeled for prednisolone effects in rats. 1,2 In human beings, pharmacodynamic modeling of glucocorticoid responses has focused on Sheiner's model 3 of linkage of a hypothetical "effect compartment" to the plasma concentration. This approach has been used to characterize the fall and return of OKT3-and OKT4-positive lymphocytes in peripheral blood after single oral doses of prednisolone. 4 A threshold concentratio...