Metabolism-based drug-drug interactions in critically ill patients: Clinical relevance & predictability of in virtro systems

Keywords: intensive care unit;drug–drug interaction;cytochrome P450;CYP3A4;enzymes;transporters;P-gp;in vitro systems;prediction systems;prescribing tools;critically ill patientsDrug–drug interactions (DDIs) contribute mainly to the incidence of adverse drug reactions. Important advances in the knowledge of human drug-metabolizing enzymes have fueled the integration of in vitro drug metabolism and clinical DDI studies for the use in drug development programs and in the clinical setting. The activities of cytochrome P450 (CYP) 3A4 and P-glycoprotein are critical determinants of drug clearance and are involved in the mechanism of numerous clinically relevant DDI. Human liver, intestinal samples, and recombinant human CYP3A4 are now available as in vitro screening tools to predict the potential for in vivo DDI. The interpretation and extrapolation of in vitro interaction data to in vivo situations require a good understanding of pharmacokinetic principles. In this chapter, research on drug metabolism and DDI along with examples illustrating the utility of specific in vitro or in vivo approaches is presented. In addition, the impact and clinical relevance of complexities such as dosing-route-dependent effects, multisite kinetics of drug-metabolizing enzymes, and non-CYP determinants of metabolic clearance are addressed.status: publishe