Are Circulating Metabolites Important in Drug-Drug Interactions? Quantitative Analysis of Risk Prediction and Inhibitory Potency

摘要

The potential of metabolites to contribute to drug-drug interactions is not well defined. The aim of this study was to determine the quantitative role of circulating metabolites in inhibitory drug-drug interactions in vivo. The AUC data for at least one circulating metabolite was available for 71% of the 102 inhibitors identified. 78% of the 80 metabolites characterized at steady state had AUCs greater than 10% of the parent drug. A comparison of the metabolite’s and parent’s [I]/Ki showed that 17 of the 21 (80%) reversible inhibitors studied had metabolites that are likely to contribute to in vivo drug-drug interactions, with some metabolites predicted to be the major inhibitors. The in vivo drug interaction risk of amiodarone, bupropion and sertraline could only be identified from in vitro data when metabolites were included into predictions. In conclusion, circulating metabolites are common with CYP inhibitors and do contribute to clinically observed CYP inhibition.