I

Excretion (urine, feces, sweat, etc.)

Figure 1 The simplest model of drug disposition inside the body.

microsomes, S9 fractions, animal and human hepatocytes, etc. These assays may also be used to check the possible formation of toxic reactive metabolites and the conditions of their production, for instance, when biotransformation processes are saturated or genetically limited.

Each pharmacodynamic effect will then be correlated with the concentrations in the corresponding organ and blood, including those of the active metabolites. This step initiates the fundamental pharmacokinetic-pharmacodynamic (PK/PD) evaluation of the drug and an assessment of its dose-concentration-effect relationships.3 Toxic effects are also correlated with the relevant concentrations measured during toxicological studies (toxicokinetics).4 In humans, PK/PD evaluations will be made using the corresponding data, quantified effects, and relevant drug levels. They will be used to define the administered dose, the number of daily administrations, drug dosage regimens, duration of treatment, etc.

Variations in drug concentrations, in parallel with a quantification of effects, may also bring to light drug-drug interactions, potentiation or antagonism, metabolic induction or inhibition, and the effects of pathological states, as discussed throughout this volume.

5.02.3 The Fate of Drugs in the Body: The Absorption, Distribution, Metabolism, and Excretion (ADME) Paradigm

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