Mechanistic modeling to predict the transporter- and enzyme-mediated drug-drug interactions of repaglinide

Pharm Res. 2013 Apr;30(4):1188-99. doi: 10.1007/s11095-012-0956-5. Epub 2013 Jan 10.


Purpose: Quantitative prediction of complex drug-drug interactions (DDIs) is challenging. Repaglinide is mainly metabolized by cytochrome-P-450 (CYP)2C8 and CYP3A4, and is also a substrate of organic anion transporting polypeptide (OATP)1B1. The purpose is to develop a physiologically based pharmacokinetic (PBPK) model to predict the pharmacokinetics and DDIs of repaglinide.

Methods: In vitro hepatic transport of repaglinide, gemfibrozil and gemfibrozil 1-O-β-glucuronide was characterized using sandwich-culture human hepatocytes. A PBPK model, implemented in Simcyp (Sheffield, UK), was developed utilizing in vitro transport and metabolic clearance data.

Results: In vitro studies suggested significant active hepatic uptake of repaglinide. Mechanistic model adequately described repaglinide pharmacokinetics, and successfully predicted DDIs with several OATP1B1 and CYP3A4 inhibitors (<10% error). Furthermore, repaglinide-gemfibrozil interaction at therapeutic dose was closely predicted using in vitro fraction metabolism for CYP2C8 (0.71), when primarily considering reversible inhibition of OATP1B1 and mechanism-based inactivation of CYP2C8 by gemfibrozil and gemfibrozil 1-O-β-glucuronide.

Conclusions: This study demonstrated that hepatic uptake is rate-determining in the systemic clearance of repaglinide. The model quantitatively predicted several repaglinide DDIs, including the complex interactions with gemfibrozil. Both OATP1B1 and CYP2C8 inhibition contribute significantly to repaglinide-gemfibrozil interaction, and need to be considered for quantitative rationalization of DDIs with either drug.

MeSH terms

  • Aryl Hydrocarbon Hydroxylases / antagonists & inhibitors
  • Aryl Hydrocarbon Hydroxylases / metabolism
  • Biological Transport, Active / drug effects
  • Carbamates / pharmacokinetics*
  • Carbamates / pharmacology
  • Cell Line
  • Cytochrome P-450 CYP2C8
  • Drug Interactions
  • Gemfibrozil / analogs & derivatives
  • Gemfibrozil / pharmacokinetics*
  • Gemfibrozil / pharmacology
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism*
  • Humans
  • Hypoglycemic Agents / pharmacokinetics*
  • Hypoglycemic Agents / pharmacology
  • Hypolipidemic Agents / chemistry
  • Hypolipidemic Agents / pharmacokinetics*
  • Hypolipidemic Agents / pharmacology
  • Liver-Specific Organic Anion Transporter 1
  • Models, Biological
  • Organic Anion Transporters / antagonists & inhibitors
  • Organic Anion Transporters / metabolism
  • Piperidines / pharmacokinetics*
  • Piperidines / pharmacology


  • Carbamates
  • Hypoglycemic Agents
  • Hypolipidemic Agents
  • Liver-Specific Organic Anion Transporter 1
  • Organic Anion Transporters
  • Piperidines
  • SLCO1B1 protein, human
  • repaglinide
  • Aryl Hydrocarbon Hydroxylases
  • CYP2C8 protein, human
  • Cytochrome P-450 CYP2C8
  • Gemfibrozil