Comparison of the inhibitory profiles of itraconazole and cimetidine in cytochrome P450 3A4 genetic variants

Takeshi Akiyoshi, Takashi Saito, Saori Murase, Mitsue Miyazaki, Norie Murayama, Hiroshi Yamazaki, F. Peter Guengerich, Katsunori Nakamura, Koujirou Yamamoto, Hisakazu Ohtani

研究成果: Article査読

22 被引用数 (Scopus)

抄録

CYP3A4, an important drug-metabolizing enzyme, is known to have genetic variants. We have previously reported that CYP3A4 variants such as CYP3A4.2, 7, 16, and 18 show different enzymatic kinetics from CYP3A4.1 (wild type). In this study, we quantitatively investigated the inhibition kinetics of two typical inhibitors, itraconazole (ITCZ) and cimetidine (CMD), on CYP3A4 variants and evaluated whether the genetic variation leads to interindividual differences in the extent of CYP3A4-mediated drug interactions. The inhibitory profiles of ITCZ and CMD on the metabolism of testosterone (TST) were analyzed by using recombinant CYP3A4 variants. The genetic variation of CYP3A4 significantly affected the inhibition profiles of the two inhibitors. In CYP3A4.7, the Ki value for ITCZ was 2.4-fold higher than that for the wild-type enzyme, whereas the Ki value for CMD was 0.64-fold lower. In CYP3A4.16, the Ki value for ITCZ was 0.54-fold lower than that for wild-type CYP3A4, whereas the Ki value for CMD was 3.2-fold higher. The influence of other genetic variations also differed between the two inhibitors. Docking simulations could explain the changes in the Ki values, based on the accessibility of TST and inhibitors to the heme moiety of the CYP3A4 molecule. In conclusion, the inhibitory effects of an inhibitor differ among CYP3A4 variants, suggesting that the genetic variation of CYP3A4 may contribute, at least in part, to interindividual differences in drug interactions mediated by CYP3A4 inhibition, and the pattern of the influences of genetic variation differs among inhibitors as well as substrates.

本文言語English
ページ(範囲)724-728
ページ数5
ジャーナルDrug Metabolism and Disposition
39
4
DOI
出版ステータスPublished - 2011 4月

ASJC Scopus subject areas

  • 薬理学
  • 薬科学

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