ABSTRACT
The safe use of drugs is dependent on the therapeutic index of each individual drug. This margin defines how much a drugs’ exposure can be increased above that required for therapy until adverse drug events might occur. Any intrinsic or extrinsic factor shifting drug exposure may result either in an altered therapeutic efficacy, through deceased exposure, or in adverse drug events due to exposure increases above the therapeutic index. Intrinsic factors may include ethnicity, gender, age, body weight, enzyme or transporter polymorphisms, and disease state, whereas typical extrinsic factors are smoking, food, beverages, and herbal–drug and drug–drug interactions (DDIs). This chapter focuses pharmacokinetic DDIs, which include effects on the activities of drug-metabolizing enzymes, drug transporters, the passive principles of physicochemical interactions, and effects modifying the binding to blood or tissue proteins. If two or more drugs are combined, DDIs may arise in both directions.
