論文

査読有り
2017年11月

Notable Drug-Drug Interaction Between Etizolam and Itraconazole in Poor Metabolizers of Cytochrome P450 2C19

JOURNAL OF CLINICAL PHARMACOLOGY
  • Takehito Yamamoto
  • ,
  • Kenichi Furihata
  • ,
  • Akihiro Hisaka
  • ,
  • Takashi Moritoyo
  • ,
  • Kazuaki Ogoe
  • ,
  • Shizuko Kusayama
  • ,
  • Keiju Motohashi
  • ,
  • Akiko Mori
  • ,
  • Takeshi Iwatsubo
  • ,
  • Hiroshi Suzuki

57
11
開始ページ
1491
終了ページ
1499
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1002/jcph.956
出版者・発行元
WILEY

In this study, impact of a polymorphism of CYP2C19 on drug-drug interaction (DDI) was examined for etizolam. The effect of itraconazole (a strong CYP3A inhibitor) on the pharmacokinetics of etizolam (a substrate of CYP2C19 and CYP3A) was assessed in both extensive metabolizers (EMs) and poor metabolizers (PMs) of CYP2C19. Sixteen participants (8 EMs and 8 PMs) received a single oral dose of etizolam (0.25mg) on day 1. The participants ingested itraconazole (200mg twice a day) on days 2-5. On day 5, participants received an oral dose of etizolam (0.25mg) again. Before coadministration of itraconazole (day 1), the area under the time-plasma concentration curve from time zero to infinity (AUC) of etizolam was higher in PMs than in EMs (2.65-fold, P<.01). Coadministration of itraconazole increased the AUC of etizolam 1.66-fold and 2.34-fold in EMs and PMs, respectively (day 5). Consequently, AUC was 6.18-fold higher in PMs with itraconazole than that in EMs without itraconazole. The increase by itraconazole was larger in PMs (P<.01). In heterozygous EMs (hEMs), AUC was simulated to be 2.56-fold higher with itraconazole than that in EMs without itraconazole. We found that in vitro measurements of fraction metabolized (f(m)) using the liver microsome prepared from PM donors would be helpful to predict polymorphism-dependent DDIs. These results suggest that the PMs and hEMs of a polymorphic CYP would be at higher risk of DDIs relative to EMs for drugs metabolized by both polymorphic and nonpolymorphic CYPs such as etizolam.

Web of Science ® 被引用回数 : 2

リンク情報
DOI
https://doi.org/10.1002/jcph.956
Web of Science
https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=JSTA_CEL&SrcApp=J_Gate_JST&DestLinkType=FullRecord&KeyUT=WOS:000412670000014&DestApp=WOS_CPL

エクスポート
BibTeX RIS