The importance of metabolite pharmacokinetics studies in drug development

摘要

Drug metabolism: basic concepts: Some drugs are eliminated from the human body (e.g., by renal, biliary or intestinal excretion) without any biotransformation. For most drugs, total or part of the dose undergoes metabolism before elimination from human body. The reactions in drug metabolism can be categorized into two types: Phase I and Phase II. Phase I metabolism is characterized as a 'functionalization' phase, which tends to generate more hydrophilic metabolites, and the metabolites can be eliminated from the human body or undergo secondary metabolism. The Phase II metabolism of drugs are conjugation reactions including glucuronidation, sulfation, glutathione conjugation and more. The most important organ for human drug metabolism is liver, and metabolism can also occur in other organs such as intestine, kidneys and lungs [1,2]. It should also be noticed that for orally administrated drugs to enter systemic circulation, an additional barrier may be the extensive metabolism in the GI tract and/or liver, which may result in a low oral bioavailability ('first-pass effect') and impair therapeutic effects [3].