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Analysis of the repaglinide concentration increase produced by gemfibrozil and itraconazole based on the inhibition of the hepatic uptake transporter and metabolic enzymes (292.2)
Author(s) -
Kudo Toshiyuki,
Hisaka Akihiro,
Sugiyama Yuchi,
Ito Kiyomi
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.292.2
Subject(s) - repaglinide , physiologically based pharmacokinetic modelling , chemistry , pharmacology , pharmacokinetics , gemfibrozil , itraconazole , transporter , biochemistry , endocrinology , metformin , medicine , cholesterol , antifungal , dermatology , gene , diabetes mellitus
The plasma concentration of repaglinide is reported to increase greatly when given after repeated oral administration of itraconazole (ICZ) and gemfibrozil (GEM). The present study analyzed this interaction based on a physiologically based pharmacokinetic (PBPK) model incorporating inhibition of the hepatic uptake transporter and metabolic enzymes involved in repaglinide disposition. Firstly, the plasma concentration profiles of inhibitors (ICZ, GEM and GEM glucuronide (GEM‐glu)) were reproduced by a PBPK model to obtain their pharmacokinetic parameters. The plasma concentration profiles of repaglinide were then analyzed by a PBPK model, together with those of the inhibitors, assuming a competitive inhibition of CYP3A4 by ICZ, mechanism‐based inhibition of CYP2C8 by GEM‐glu, and inhibition of OATP1B1 by GEM and GEM‐glu. The plasma concentration profiles of repaglinide were well reproduced by the PBPK model and the validity of the obtained parameters was confirmed by sensitivity analyses and by reproducing the repaglinide/GEM interaction in the cases of different dosing schedules. The present findings suggested that the reported concentration increase of repaglinide, suggestive of synergistic effects of the co‐administered inhibitors, can be quantitatively explained by the simultaneous inhibition of the multiple clearance pathways of repaglinide.