Selection of the right dose is a major problem in drug therapy because following administration of the same dose of a drug to a patient population drug response varies substantially. A major factor responsible for variability in drug response is the activity of drug metabolising enzymes. The variability in the drug elimination process poses problems especially in the early phase of drug development. If a drug is mainly metabolised by an enzyme which exhibits a genetic polymorphism it is not unusual that a 50 fold difference in plasma concentrations will be observed if the same drug dosage is used. Thus during preclinical development of a drug and prior to its first administration to humans one would like to know the following facts about the drug. How is the drug eliminated from the body and which fraction of the dose is cleared by metabolism. If metabolism is the predominant route of elimination one can predict substantial variability in its clearance due to the wellknown interindividual variation in the activity of drug metabolising enzymes. Less variability in clearance, however, will be observed if the drug is renally excreted because in subjects with normal kidney function only small interindividual differences in renal clearance occur. It is also of interest to know which enzymes (cytochrome P450s or the various phase II enzymes) catalyse the biotrans-formation of the drug. Furthermore we are interested to know the contribution of the different pathways to total metabolic clearance and what CYPs are involved in the formation of the different metabolites. Based on the knowledge of the enzymes involved in the biotransformation of a drug and knowing the expression of the enzymes in the liver we can make an educated guess about the contribution of liver to the metabolism of the drug under study.
