2013年2月
Analysis of the repaglinide concentration increase produced by gemfibrozil and itraconazole based on the inhibition of the hepatic uptake transporter and metabolic enzymes.
Drug metabolism and disposition: the biological fate of chemicals
- ,
- ,
- ,
- 巻
- 41
- 号
- 2
- 開始ページ
- 362
- 終了ページ
- 71
- 記述言語
- 英語
- 掲載種別
- 研究論文(学術雑誌)
- DOI
- 10.1124/dmd.112.049460
- 出版者・発行元
- AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
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.
- リンク情報
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- DOI
- https://doi.org/10.1124/dmd.112.049460
- J-GLOBAL
- https://jglobal.jst.go.jp/detail?JGLOBAL_ID=201502865393994371
- PubMed
- https://www.ncbi.nlm.nih.gov/pubmed/23139378
- Web of Science
- https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=JSTA_CEL&SrcApp=J_Gate_JST&DestLinkType=FullRecord&KeyUT=WOS:000315352400015&DestApp=WOS_CPL
- ID情報
-
- DOI : 10.1124/dmd.112.049460
- ISSN : 0090-9556
- J-Global ID : 201502865393994371
- PubMed ID : 23139378
- Web of Science ID : WOS:000315352400015