Time-dependent kinetics

When the pharmacokinetic behavior of the drug changes with time, this is also considered nonlinear pharmacokinetics.

a- Autoinduction:

Some drugs such as carbamazepine (CBZ) can induce its own metabolism. This means that CBZ clearance increases with time during multiple CBZ administration.

After initiation of CBZ therapy, plasma CBZ conc approaches the steady state conc.

The total body clearance of CBZ increases during multiple administration due to autoinduction and the drug conc decreases gradually until lower steady state conc is achieved.

b- Product inhibition:

Some drugs are metabolized to metabolites that can compete with the parent drug for the same metabolic pathways.

Isosorbide denitrate is metabolized by denitration to isosorbide-2-mononitrate and isosorbide-5-mononitrate. These metabolites can compete with the parent drug for the denitration pathway resulting in slower rate of parent drug metabolism.

The metabolite competitively inhibits the metabolism of the parent drug. Because the conc of the metabolite is changing with time, the inhibitory effect of the metabolite on the elimination of the patent drug changes with time.

The inhibition of the parent drug metabolism by the metabolite is dependent on the metabolite conc. The rate of drug elimination is slower when the metabolite cone is high. Then as the metabolite cone gets lower, the drug elimination rate becomes faster.

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