Mini-series: I. Basic science. Uncertainty and inaccuracy of predicting CYP-mediated in vivo drug interactions in the ICU from in vitro models: focus on CYP3A4.

Drug-drug interactions (DDIs) contribute significantly 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 DDIs studies for use in drug development programs and in the clinical setting. The activity of cytochrome P450 (CYP) 3A4 and P-glycoprotein are critical determinant of drug clearance, interindividual variability in drug disposition and clinical efficacy, and appears to be involved in the mechanism of numerous clinically relevant DDIs. Cell-based in vitro models are being increasingly applied in elucidating the pharmacokinetic profile of drug candidates during the preclinical steps of drug development. Human liver, intestinal samples and recombinant human CYP3A4 are now readily available as in vitro screening tools to predict the potential for in vivo DDIs. Although it is easy to determine in vitro metabolic DDIs, the interpretation and extrapolation of in vitro interaction data to in vivo situations requires a good understanding of pharmacokinetic principles. Clinicians and pharmacokineticists should recognize that in vitro models may not be clinically relevant in all situations. In the current article, research will be presented on drug metabolism and DDIs along with examples illustrating the utility of specific in vitro or in vivo approaches. In addition, the impact and clinical relevance of complexities such as dosing-route dependent effects, multi-site kinetics of drug-metabolizing enzymes and non-CYP determinants of metabolic clearance will be addressed.