Inhibition of CYP3A4 and CYP2C9 by podophyllotoxin: Implication for clinical drug–drug interactions

被引：0
|
作者：
Jin-Hui Song
Dong-Xue Sun
Bin Chen
Dai-Hong Ji
Jie Pu
Jie Xu
Feng-De Tian
Lin Guo
机构：
[1] Affiliated Zhongshan Hospital of Dalian University,Orthopedics Department 2
[2] Shenyang Pharmaceutical University,School of Traditional Chinese Medicine
[3] Affiliated Zhongshan Hospital of Dalian University,The Nursing Department
来源：
Journal of Biosciences | 2011年 / 36卷
关键词：
Cytochrome P450 (CYP); drug–drug interaction (DDI); podophyllotoxin (PPT); time-dependent inhibition (TDI);
D O I：
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中图分类号：
学科分类号：
摘要：
Podophyllotoxin (PPT) and its derivatives exert significant anti-cancer activities, and one derivative etoposide is often utilized to treat various cancers in the clinic. The aim of the present study is to investigate the inhibitory effects of PPT on major cytochrome P450 (CYP) isoforms in human livers. Inhibition of CYP3A4, CYP2C9, CYP2C8, CYP2D6, CYP2E1 and CYP2A6 by PPT was investigated in the human liver microsomal system. Time-dependent inhibition of CYP3A4 by PPT was also evaluated. The results showed that PPT strongly exhibited inhibitory effects on CYP3A4 and CYP2C9 in a concentration-dependent manner. Half inhibition concentration (IC50) was 1.1 ± 0.3 and 4.6 ± 0.3 μM for CYP3A4 and CYP2C9, respectively. Inhibition kinetic analysis showed that PPT exhibited competitive inhibition towards CYP3A4 and CYP2C9 with Ki of 1.6 and 2.0 μM, respectively. Additionally, PPT exerted time-dependent inhibition towards CYP3A4 and the kinetic parameters were 4.4 ± 2.1 μM and 0.06 ± 0.01 min–1 for KI and kinact, respectively. Our experimental data indicate that potential drug–drug interaction (DDI) might exist when PPT is co-administered with the substrates which mainly undergo CYP3A4- or CYP2C9-mediated metabolism.
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页码：879 / 885
页数：6
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