Mechanisms underlying variability in response to drug therapy: implications for amiodarone use

Abstract

Drug disposition can be described by the traditional processes of absorption, distribution, metabolism, and elimination. A contemporary view of these processes includes the concept that they are determined by the regulated activity of specific gene products. Such a view is an important step to an increased understanding of interindividual variability in drug disposition and in response to drug therapy. In addition, molecular mechanisms underlying common drug interactions are now being elucidated. Despite this new knowledge, little is understood about the molecular mechanisms determining the unusual pharmacokinetic and pharmacodynamic profile of amiodarone. These unusual characteristics include incomplete bioavailability, distribution to multiple tissue sites, extreme lipophilicity, biotransformation to an active metabolite, and very slow elimination of both parent drug and active metabolite. The drug also produces a range of important pharmacologic effects, including antiadrenergic effects that are apparent early during therapy, changes in cardiac repolarization that take longer to develop, and important extracardiac actions, including side effects and drug interactions. As a consequence of these pharmacokinetic and pharmacodynamic complexities, individualization of dose during long-term therapy with amiodarone has not been systematically explored.