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 t1/2 at Lower Concentrations Only (Levy, 1965)

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

Aspirin Metabolism

Diagram 21.4.1 Scheme for Aspirin/Salicylate Elimination

In the case of aspirin we have parallel first order processes and Michaelis-Menten processes. 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).

First order and MM Kinetics

Figure 21.4.2 Plot of Apparent t1/2 Versus log(DOSE) (Niazi, 1979)

At low doses the t1/2 could be calculated from km and Vm/Km.

t1/2 = 0.693/(0.15 + 7/10) = 0.82 hr

At high dose the contribution from the saturable metabolism is less significant and the t1/2 can be estimated from km alone.

t1/2 = 0.693/0.15 = 4.6 hr

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

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