title: Analysis of the repaglinide concentration increase produced by gemfibrozil and itraconazole based on the inhibition of the hepatic uptake transporter and metabolic enzymes.
abstract: The plasma concentration of repaglinide is reported to increase greatly when given after repeated oral administration of itraconazole and gemfibrozil. 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 (itraconazole, gemfibrozil, and gemfibrozil glucuronide) 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 itraconazole, mechanism-based inhibition of CYP2C8 by gemfibrozil glucuronide, and inhibition of organic anion transporting polypeptide (OATP) 1B1 by gemfibrozil and its glucuronide. The plasma concentration profiles of repaglinide were well reproduced by the PBPK model based on the above assumptions, and the optimized values for the inhibition constants (0.0676 nM for itraconazole against CYP3A4; 14.2 μM for gemfibrozil against OATP1B1; and 5.48 μM for gemfibrozil glucuronide against OATP1B1) and the fraction of repaglinide metabolized by CYP2C8 (0.801) were consistent with the reported values. The validity of the obtained parameters was further confirmed by sensitivity analyses and by reproducing the repaglinide concentration increase produced by concomitant gemfibrozil administration at various timings/doses. The present findings suggested that the reported concentration increase of repaglinide, suggestive of synergistic effects of the coadministered inhibitors, can be quantitatively explained by the simultaneous inhibition of the multiple clearance pathways of repaglinide.
authors.affiliation: Research Institute of Pharmaceutical Sciences, Musashino University, Tokyo, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Kudo
authors.forename: Akihiro
authors.initials: A
authors.lastname: Hisaka
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Sugiyama
authors.forename: Kiyomi
authors.initials: K
authors.lastname: Ito
mesh_terms: D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001711:Biotransformation; D002219:Carbamates / Q000097:blood / Q000493:pharmacokinetics*; D003198:Computer Simulation; D065727:Cytochrome P-450 CYP2C8; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D015248:Gemfibrozil / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D020719:Glucuronides / Q000494:pharmacology; D006801:Humans; D007004:Hypoglycemic Agents / Q000097:blood / Q000493:pharmacokinetics*; D017964:Itraconazole / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D016018:Least-Squares Analysis; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D027381:Liver-Specific Organic Anion Transporter 1; D008954:Models, Biological; D017711:Nonlinear Dynamics; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010880:Piperidines / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D002219:Carbamates; D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors; D020719:Glucuronides; D007004:Hypoglycemic Agents; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; D010880:Piperidines; C503999:SLCO1B1 protein, human; D017964:Itraconazole; C072379:repaglinide; D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; D065727:Cytochrome P-450 CYP2C8; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D015248:Gemfibrozil