Mechanisms of Drug Interactions I: Absorption, Metabolism, and Excretion

Understanding the basic mechanisms of drug interactions allows ­researchers and clinicians to best interpret and apply drug interaction data, and make predictions about patient-specific interactions. Drug interactions can occur at the site of action (pharmacodynamic interactions), and during the absorption, ­distribution, metabolism and excretion phases of drug distribution (pharmacokinetic interactions). The consequences of unintended interactions can be extremely harmful and potentially fatal, such as those leading to cardiac conduction abnormalities. Knowledge of the mechanisms of drug interactions has also identified ­useful interactions with therapeutic benefits, such as in the development of feasible dosing regimens for protease inhibitors in the treatment of HIV infection. This chapter describes the mechanisms of drug interactions for each of the aforementioned pharmacokinetic processes. The cytochrome P450 family of enzymes, the P-glycoprotein drug transporter, and their mechanisms for inhibition, induction, and suppression are reviewed. Preclinical methods used to study cytochrome P450 are discussed. The chemical and physiologic changes that affect absorption and elimination, and how they are influenced by drugs, are explained.