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.
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.
Authors: Mikko Niemi; Janne T Backman; Lauri I Kajosaari; Julian B Leathart; Mikko Neuvonen; Ann K Daly; Michel Eichelbaum; Kari T Kivistö; Pertti J Neuvonen Journal: Clin Pharmacol Ther Date: 2005-06 Impact factor: 6.875
Authors: Julia Kirchheiner; Ivar Roots; Mark Goldammer; Bernd Rosenkranz; Jürgen Brockmöller Journal: Clin Pharmacokinet Date: 2005 Impact factor: 6.447
Authors: Brian W Ogilvie; Donglu Zhang; Wenying Li; A David Rodrigues; Amy E Gipson; Jeff Holsapple; Paul Toren; Andrew Parkinson Journal: Drug Metab Dispos Date: 2005-11-18 Impact factor: 3.922
Authors: P N van Heiningen; V Hatorp; K Kramer Nielsen; K T Hansen; J J van Lier; N C De Merbel; B Oosterhuis; J H Jonkman Journal: Eur J Clin Pharmacol Date: 1999-09 Impact factor: 2.953
Authors: Lauri I Kajosaari; Mikko Niemi; Mikko Neuvonen; Jouko Laitila; Pertti J Neuvonen; Janne T Backman Journal: Clin Pharmacol Ther Date: 2005-10 Impact factor: 6.875
Authors: Josiane de Oliveira Cardoso; Regina Vincenzi Oliveira; Jessica Bo Li Lu; Zeruesenay Desta Journal: Drug Metab Dispos Date: 2015-12 Impact factor: 3.922
Authors: Stephen Fowler; Peter N Morcos; Yumi Cleary; Meret Martin-Facklam; Neil Parrott; Michael Gertz; Li Yu Journal: Curr Pharmacol Rep Date: 2017-02-01