Functional characterization of drug uptake and metabolism in the heart.

INTRODUCTION: Evaluation of kinetics of uptake into the heart could be important for the efficacy and toxicity of cardioactive drugs. Although recent advances in molecular biology have identified cardiac uptake and efflux transporters as well as drug-metabolizing enzymes, little is known about their functional properties in situ. AREAS COVERED: The modeling of cardiac pharmacokinetics and pharmacodynamics (PK/PD) is overviewed with respect to experimental designs. Also covered is the role of myocardial uptake and binding processes for pharmacologic effect kinetics in relation to cardiac drugs. An update is given on the role of transport processes for the acute myocardial uptake of drugs and the impact on the time course of pharmacodynamic effects, as well as the interaction of drugs with CYP enzymes in myocytes. EXPERT OPINION: Depending on physicochemical properties, drugs are relatively rapidly taken up by the heart. It is important to realize that interstitial concentration is determinative when cardiac drugs act via cell membrane receptors. The role of uptake and efflux transporters in myocardial uptake of drugs is not yet clearly defined. Kinetic modeling of receptor-mediated pharmacodynamics may provide useful information on receptor binding and transduction processes. Inhibition or induction of cardiac CYP by drugs can cause changes in the metabolism of endogenous substances and thus influence cardiac function.