Metabolism or decay of a drug prior to, during or shortly after its enteral absorption necessarily reduces the amount of unchanged drug reaching the systemic circulation. This influences the pharmacokinetic properties of a drug and is called first-pass effect. Every drug metabolized in the liver theoretically undergoes a first-pass metabolism after enteral application. Whether it results in a pharmacokinetically obvious first-pass effect depends on extent and rate of this metabolic step. The pharmacokinetic relevance of a first-pass effect does not automatically mean also its therapeutic relevance. For the assessment of the therapeutic relevance of a first-pass effect, extent and slope of its dose-effect curve in man and the therapeutic index of a drug must be taken into accounts.