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

نویسندگان

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

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 K(i) value for ITCZ was 2.4-fold higher than that for the wild-type enzyme, whereas the K(i) value for CMD was 0.64-fold lower. In CYP3A4.16, the K(i) value for ITCZ was 0.54-fold lower than that for wild-type CYP3A4, whereas the K(i) 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 K(i) 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.

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عنوان ژورنال:
  • Drug metabolism and disposition: the biological fate of chemicals

دوره 39 4  شماره 

صفحات  -

تاریخ انتشار 2011