Repaglinide-gemfibrozil drug interaction: inhibition of repaglinide glucuronidation as a potential additional contributing mechanism

Br J Clin Pharmacol. 2010 Dec;70(6):870-80. doi: 10.1111/j.1365-2125.2010.03772.x.


Aim: To further explore the mechanism underlying the interaction between repaglinide and gemfibrozil, alone or in combination with itraconazole.

Methods: Repaglinide metabolism was assessed in vitro (human liver subcellular fractions, fresh human hepatocytes, and recombinant enzymes) and the resulting incubates were analyzed, by liquid chromatography-mass spectrometry (LC-MS) and radioactivity counting, to identify and quantify the different metabolites therein. Chemical inhibitors, in addition to a trapping agent, were also employed to elucidate the importance of each metabolic pathway. Finally, a panel of human liver microsomes (genotyped for UGT1A1*28 allele status) was used to determine the importance of UGT1A1 in the direct glucuronidation of repaglinide.

Results: The results of the present study demonstrate that repaglinide can undergo direct glucuronidation, a pathway that can possibly contribute to the interaction with gemfibrozil. For example, [³H]-repaglinide formed glucuronide and oxidative metabolites (M2 and M4) when incubated with primary human hepatocytes. Gemfibrozil effectively inhibited (∼78%) both glucuronide and M4 formation, but had a minor effect on M2 formation. Concomitantly, the overall turnover of repaglinide was also inhibited (∼80%), and was completely abolished when gemfibrozil was co-incubated with itraconazole. These observations are in qualitative agreement with the in vivo findings. UGT1A1 plays a significant role in the glucuronidation of repaglinide. In addition, gemfibrozil and its glucuronide inhibit repaglinide glucuronidation and the inhibition by gemfibrozil glucuronide is time-dependent.

Conclusions: Inhibition of UGT enzymes, especially UGT1A1, by gemfibrozil and its glucuronide is an additional mechanism to consider when rationalizing the interaction between repaglinide and gemfibrozil.

MeSH terms

  • Biotransformation
  • Carbamates / pharmacokinetics
  • Carbamates / pharmacology*
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Gemfibrozil / pharmacology*
  • Glucuronides / metabolism
  • Glucuronosyltransferase / physiology
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism
  • Humans
  • Hypoglycemic Agents / pharmacokinetics
  • Hypoglycemic Agents / pharmacology*
  • Hypolipidemic Agents / pharmacology*
  • Itraconazole / pharmacology
  • Microsomes, Liver / metabolism
  • Piperidines / pharmacokinetics
  • Piperidines / pharmacology*


  • Carbamates
  • Glucuronides
  • Hypoglycemic Agents
  • Hypolipidemic Agents
  • Piperidines
  • Itraconazole
  • repaglinide
  • UGT1A1 enzyme
  • Glucuronosyltransferase
  • Gemfibrozil