THE USE OF IN-VITRO METABOLISM TECHNIQUES IN THE PLANNING AND INTERPRETATION OF DRUG SAFETY STUDIES

An important issue in toxicology is the suitability of the data obtain ed with experimental animals for human risk assessment. Because it is not possible to use humans in long-term toxicological studies, the use of animals will continue. However, the data obtained in animal studie s can be better extrapolated to the patient by utilizing bridging stud ies with in vitro models of human drug metabolism. There are 2 basic c ategories of in vitro methods for the examination of human liver drug metabolism. The first group of in vitro methods consists of the cellul ar models, which include primary hepatocytes, liver slices, and cell l ines. The second group is the use of preparations of the drug-metaboli zing enzymes such as tissue homogenates, subcellular fractions, and is olated enzymes. Studies modeling both the human and experimental anima l metabolism of a drug are useful in the design of toxicological studi es. In vitro studies can identify metabolites, species-specific metabo lic routes, and the experimental animal model that best reflects the p otential human exposure to the drug and its metabolites. This informat ion can also be useful in the design of the clinical studies by identi fying human metabolites, the enzymes responsible for the metabolic cle arance of the drug, the effects of genetics and other host factors on the metabolism of the drug, and potential drug-drug interactions. An e xample of how such information is generated and interpreted is present ed.