Are circulating metabolites important in drug-drug interactions?: Quantitative analysis of risk prediction and inhibitory potency

Clin Pharmacol Ther. 2011 Jan;89(1):105-13. doi: 10.1038/clpt.2010.252. Epub 2010 Dec 1.


The potential of metabolites to contribute to drug-drug interactions (DDIs) is not well defined. The aim of this study was to determine the quantitative role of circulating metabolites in inhibitory DDIs in vivo. The area under the plasma concentration-time curve (AUC) data related to at least one circulating metabolite was available for 71% of the 102 inhibitor drugs identified. Of the 80 metabolites characterized at steady state, 78% had AUCs >10% of that of the parent drug. A comparison of the inhibitor concentration/inhibition constant ([I]/K(i)) ratios of metabolites and the respective parent drugs showed that 17 of the 21 (80%) reversible inhibitors studied had metabolites that were likely to contribute to in vivo DDIs, with some metabolites predicted to have inhibitory effects greater than those of the parent drug. The in vivo drug interaction risks associated with amiodarone, bupropion, and sertraline could be identified from in vitro data only, when data pertaining to metabolites were included in the predictions. In conclusion, cytochrome P450 (CYP) inhibitors often have circulating metabolites that contribute to clinically observed CYP inhibition.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms
  • Amiodarone / blood
  • Amiodarone / pharmacokinetics
  • Area Under Curve
  • Biomarkers, Pharmacological / blood
  • Biotransformation*
  • Bupropion / blood
  • Bupropion / pharmacokinetics
  • Cytochrome P-450 Enzyme Inhibitors
  • Databases, Factual
  • Drug Interactions*
  • Enzyme Inhibitors / blood*
  • Enzyme Inhibitors / pharmacokinetics*
  • Guidelines as Topic
  • Humans
  • Models, Biological
  • Sertraline / blood
  • Sertraline / pharmacokinetics
  • Toxicity Tests / methods*
  • Toxicity Tests / standards
  • United States
  • United States Food and Drug Administration


  • Biomarkers, Pharmacological
  • Cytochrome P-450 Enzyme Inhibitors
  • Enzyme Inhibitors
  • Bupropion
  • Amiodarone
  • Sertraline