title: Repaglinide-gemfibrozil drug interaction: inhibition of repaglinide glucuronidation as a potential additional contributing mechanism.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Pharmaceutical Candidate Optimization, Princeton, NJ, USA. jinping.gan@bms.com
authors.forename: Jinping
authors.initials: J
authors.lastname: Gan
authors.forename: Weiqi
authors.initials: W
authors.lastname: Chen
authors.forename: Hong
authors.initials: H
authors.lastname: Shen
authors.forename: Ling
authors.initials: L
authors.lastname: Gao
authors.forename: Yang
authors.initials: Y
authors.lastname: Hong
authors.forename: Yuan
authors.initials: Y
authors.lastname: Tian
authors.forename: Wenying
authors.initials: W
authors.lastname: Li
authors.forename: Yueping
authors.initials: Y
authors.lastname: Zhang
authors.forename: Yuwei
authors.initials: Y
authors.lastname: Tang
authors.forename: Hongjian
authors.initials: H
authors.lastname: Zhang
authors.forename: William Griffith
authors.initials: WG
authors.lastname: Humphreys
authors.forename: A David
authors.initials: AD
authors.lastname: Rodrigues
mesh_terms: D001711:Biotransformation; D002219:Carbamates / Q000493:pharmacokinetics / Q000494:pharmacology*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D015248:Gemfibrozil / Q000494:pharmacology*; D020719:Glucuronides / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000502:physiology; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D017964:Itraconazole / Q000494:pharmacology; D008862:Microsomes, Liver / Q000378:metabolism; D010880:Piperidines / Q000493:pharmacokinetics / Q000494:pharmacology*; D000099148:UGT1A1 Enzyme
chemical_list: D002219:Carbamates; D015248:Gemfibrozil; D020719:Glucuronides; D014453:Glucuronosyltransferase; D007004:Hypoglycemic Agents; D000960:Hypolipidemic Agents; D017964:Itraconazole; D010880:Piperidines; D000099148:UGT1A1 Enzyme; C072379:repaglinide