Multiple inhibition mechanisms and prediction of drug-drug interactions: status of metabolism and transporter models as exemplified by gemfibrozil-drug interactions

Pharm Res. 2008 May;25(5):1063-74. doi: 10.1007/s11095-007-9446-6. Epub 2007 Sep 27.


Purpose: To assess the consequences of multiple inhibitors and differential inhibition mechanisms on the prediction of 12 gemfibrozil drug-drug interactions (DDIs). In addition, qualitative zoning of transporter-related gemfibrozil and cyclosporine DDIs was investigated.

Methods: The effect of gemfibrozil and its acyl-glucuronide on different enzymes was incorporated into a metabolic prediction model. The impact of CYP2C8 time-dependent inhibition by gemfibrozil acyl-glucuronide was assessed using repaglinide, cerivastatin, loperamide, rosiglitazone and pioglitazone DDIs. Gemfibrozil and cyclosporine inhibition data obtained in human embryonic kidney cells expressing OATP1B1 and hepatic input concentration ([I]in) were used for qualitative zoning of 14 transporter-mediated DDIs.

Results: Incorporation of time-dependent inhibition by gemfibrozil glucuronide showed no significant improvement in the prediction, as CYP2C8 contributed <65% to the overall elimination of the victim drugs investigated. Qualitative zoning of OATP1B1 DDIs resulted in no false negative predictions; yet the magnitude of observed interactions was significantly over-predicted.

Conclusions: Time-dependent inhibition by gemfibrozil glucuronide is only important for victim drugs eliminated predominantly (>80%) via CYP2C8. Qualitative zoning of OATP1B1 inhibitors based on [I]in/K (i) is valid in drug screening to avoid false negatives. Refinement of the transporter model by incorporating the fraction of drug transported by a particular transporter is recommended.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Area Under Curve
  • Aryl Hydrocarbon Hydroxylases / antagonists & inhibitors
  • Aryl Hydrocarbon Hydroxylases / metabolism
  • Carrier Proteins / metabolism
  • Cell Line
  • Cyclosporine / adverse effects
  • Cyclosporine / pharmacokinetics
  • Cytochrome P-450 CYP2C8
  • Databases, Factual
  • Drug Interactions*
  • Enzyme Inhibitors / pharmacology
  • Gemfibrozil / adverse effects*
  • Gemfibrozil / pharmacokinetics*
  • Glucuronides / metabolism
  • Humans
  • Hypolipidemic Agents / adverse effects*
  • Hypolipidemic Agents / pharmacokinetics*
  • Immunosuppressive Agents / adverse effects
  • Immunosuppressive Agents / pharmacokinetics
  • Kinetics
  • Predictive Value of Tests


  • Carrier Proteins
  • Enzyme Inhibitors
  • Glucuronides
  • Hypolipidemic Agents
  • Immunosuppressive Agents
  • Cyclosporine
  • Aryl Hydrocarbon Hydroxylases
  • CYP2C8 protein, human
  • Cytochrome P-450 CYP2C8
  • Gemfibrozil