[Capacity limited pharmacokinetics, a mechanism of drug toxicity (author's transl)]

In the past drug elimination was described mainly by two different laws. Zero-order kinetics postulates that the speed of elimination be constant and independent of drug concentration; in first-order kinetics which describes satisfactorily the elimination of all drugs except ethyl alcohol it is assumed that the speed of the elimination is proportional to the plasma drug concentration. This can only be interpreted biologically in the case of polar drugs eliminated by diffusion or filtration. Non-polar drugs, however, bind reversibly to macromolecules such as albumin and enzymes. This means that elimination should be saturable as predicted by the law of mass-action. Saturation phenomena have clearly been demonstrated with several drugs eliminated by tubular and biliary secretion, or by enzymatic transformation. It is shown that zero-order and first-order kinetics are consequences of the validity of the mass-action law in two extremely different drug concentration ranges. When the affinity between drug and biological macromolecules is high the possible clinically relevant consequences are abnormal drug accumulation and drug interactions such as mutual displacement from the plasma albumin binding sites, inhibition of active drug transport and metabolism, or enzyme induction.