PHAR 7632 Chapter 21

Non-Linear Pharmacokinetic Models

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Parallel Pathway

Figure 21.4.1 Plot of Salicylate Amount in the Body Versus Time. Similar t_1/2 at Lower Concentrations Only (Levy, 1965)

Another drug with saturable elimination kinetics is aspirin or maybe more correctly salicylate. In the case of aspirin or salicylate poisoning the elimination maybe much slower than expected because of Michaelis-Menten kinetics as shown in Diagram 21.4.1. This should be considered in any poisoning case.

Diagram 21.4.1 Scheme for Aspirin/Salicylate Elimination

In the case of aspirin we have parallel first order process with the Michaelis-Menten kinetics. Therefore as dose and consequently the concentrations increase proportionally more drug would be removed by the first order processes rather than the saturable one. This is shown in the figure below (Figure 21.4.2).

Figure 21.4.2 Plot of Apparent t_1/2 Versus log(DOSE) (Niazi, 1979)

The phenomena of non-linear pharmacokinetics is of great importance in multiple dose therapy in which more significant changes in the plateau levels are produced by the accumulation of drug in the body than can be expected in single dose studies. This accumulation will result in toxic responses especially when the therapeutic index of the drug is low.

References

Levy, G. 1965. J. Pharm. Sci., 54, 959
Niazi, S. 1979 Textbook of Biopharmaceutics and Clinical Pharmacokinetics, Appleton-Century-Crofts, New York, NY, Fig 7.14 p 181

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