Oxidative Metabolism of Tacrolimus and its Metabolite by Human Cytochrome P450 3A Subfamily.

• SHIRAGA Toshifumi

  Biopharmaceutical and Pharmacokinetic Research Laboratories, Fujisawa Pharmaceutical Co., Ltd

• NIWA Toshiro

  Biopharmaceutical and Pharmacokinetic Research Laboratories, Fujisawa Pharmaceutical Co., Ltd

• TERAMURA Yoshinori

  Biopharmaceutical and Pharmacokinetic Research Laboratories, Fujisawa Pharmaceutical Co., Ltd

• KAGAYAMA Akira

  Biopharmaceutical and Pharmacokinetic Research Laboratories, Fujisawa Pharmaceutical Co., Ltd

• TSUTSUI Michio

  Central Laboratory, Amersham K. K

• OHNO Yasuo

  National Institute of Hygienic Sciences

• IWASAKI Kazuhide

  Biopharmaceutical and Pharmacokinetic Research Laboratories, Fujisawa Pharmaceutical Co., Ltd

抄録

The cytochromes P450 (CYPs) responsible for the oxidative metabolism of tacrolimus and its in vitro major metabolite M-I, the 13-O-mono-demethylated metabolite, were characterized in human liver microsomes. Human liver microsomes and ten human CYPs expressed in Hep G2 cells were used in the experiments.<BR> 1. When ¹⁴C-labeled tacrolimus (¹⁴C-tacrolimus) was incubated with human liver microsomes, M-I formation was mainly observed in the early stage of incubation, while many peaks of the more polar metabolites, including M-VII, the 13, 15-O-di-demethylated metabolite, were detected in the late stage of incubation. When the microsomes were incubated with ¹⁴C-M-I, formation of M-VII and unidentified metabolites were observed. The rates of formation of M-I from ¹⁴C-tacrolimus in 10 different human liver microsomes correlated well with the activities of testosterone 6β-hydroxylation and tolbutamide methyl-hydroxylation, but not with the marker enzyme activities of other CYPs. The metabolism of both tacrolimus and M-I by human liver microsomes were inhibited by ketoconazole and anti-CYP3A4 antiserum.<BR> 2. After incubation of ¹⁴C-tacrolimus with Hep G2 cell lysates containing expressed human CYPs, M-I formation was observed in the reaction system with CYP3A3, 3A4 and 3A5, but not with CYP1A2, 2A6, 2B6, 2C8, 2C9, 2D6 or 2E1. After incubation of the lysates with ¹⁴C-M-I, M-VII formation was again observed only in the system with the CYP3A subfamily. Substrate disappearance of both tacrolimus and M-I was the most efficiently catalyzed by CYP3A4.<BR> 3. These results suggest that tacrolimus is metabolized to polar metabolites through M-I by human liver microsomes, and that the metabolism of both tacrolimus and M-I are mainly catalyzed by CYP3A4.

収録刊行物

• 薬物動態

  薬物動態 14 (4), 277-285, 1999

  日本薬物動態学会

キーワード

• Tacrolimus
• Metabolism
• Human cytochrome P450
• CYP3A
• Vaccinia virus

詳細情報

• CRID: 1390282679646301056
• NII論文ID: 10008199592
• NII書誌ID: AN10144117
• DOI: 10.2133/dmpk.14.277
• ISSN: 09161139
• Web Site: http://www.jstage.jst.go.jp/article/dmpk1986/14/4/14_4_277/_pdf
• 本文言語コード: en
• データソース種別:
  • JaLC
  • Crossref
  • CiNii Articles
• 抄録ライセンスフラグ: 使用不可