- 著者
- Takeshi AKIYOSHI Marie ITO Saori MURASE Mitsue MIYAZAKI F. Peter GUENGERICH Katsunori NAKAMURA Koujirou YAMAMOTO Hisakazu OHTANI
- 出版者
- 日本薬物動態学会 会長/日本薬物動態学会 DMPK編集委員長
- 雑誌
- Drug Metabolism and Pharmacokinetics (ISSN:13474367)
- 巻号頁・発行日
- vol.28, no.5, pp.411-415, 2013 (Released:2013-10-25)
- 参考文献数
- 31
- 被引用文献数
- 21
Inhibition of cytochrome P450 (CYP) 3A4 is the major cause of drug-drug interactions (DDI). We have previously reported that the genetic variation of CYP3A4 significantly affected the inhibitory profiles of typical competitive inhibitors. In addition to competitive inhibition, some clinically significant DDI are attributable to mechanism-based inhibition (MBI). However, the differences in the MBI kinetics among CYP3A4 genetic variants remain to be characterized. In this study, we quantitatively investigated the inhibition kinetics of MBI inhibitors, erythromycin and clarithromycin, on the CYP3A4 variants CYP3A4.1, 4.2, 4.7, 4.16, and 4.18. The activity of CYP3A4 was assessed using testosterone 6β-hydroxylation with recombinant CYP3A4. Both erythromycin and clarithromycin decreased the activity of CYP3A4 in a time-dependent manner. The maximum inactivation rate constants, kinact,max, of erythromycin for CYP3A4.2 and CYP3A4.7 were 0.5-fold that for CYP3A4.1, while that for CYP3A4.16 and CYP3A4.18 were similar to that for CYP3A4.1. The KI values of erythromycin for CYP3A4.2, 4.7, 4.16, and 4.18 were 1.2-, 0.4-, 2.2- and 0.72-fold those of CYP3A4.1, respectively. Similar results were obtained for clarithromycin. In conclusion, the inhibitory profiles of MBI inhibitors, as well as competitive inhibitors, may possibly differ among CYP3A4 variants. This difference may contribute to interindividual differences in the extent of DDI based on MBI.
- 著者
- Yuki Kondo Sachimi Yoshihashi Kayo Mimori Ruri Ogihara Yoshinori Kanehama Yoshiyuki Maki Shin Enosawa Kouichi Kurose Takahiro Iwao Katsunori Nakamura Tamihide Matsunaga
- 出版者
- 日本薬物動態学会 会長/日本薬物動態学会 DMPK編集委員長
- 雑誌
- Drug Metabolism and Pharmacokinetics (ISSN:13474367)
- 巻号頁・発行日
- pp.DMPK-14-RG-022, (Released:2014-04-29)
- 参考文献数
- 22
- 被引用文献数
- 9
This study aimed to establish culture conditions which are able to give the differentiation of induced pluripotent (iPS) cells to the hepatocytes. To this end, we examined the usefulness of culture medium containing the components involved in the intermediary metabolism in the liver. More specifically, we examined the effect of the 'modified L-15 medium' containing galactose, phenylalanine and ornitine, but deprived of glucose, tyrosine, arginine and pyruvic acid. The medium was altered according to changes in the expression of enzymes that participate in liver-specific pathways. After 25 days of differentiation, the differentiated cells expressed hepatocyte markers and drug-metabolizing enzymes. These expression levels were increased using modified L-15 medium. The survival of human fetal liver cells and the death of human fibroblasts were observed during culture in modified L-15 medium. Most of the cells that differentiated from human iPS cells using modified L-15 medium were stained by anti-human albumin antibody. These results suggest that iPS cells can be converted to high purity-differentiated hepatocytes by cultivating them in modified L-15 medium.