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

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 liv...

Full description

Saved in:
Bibliographic Details
Published in:Journal of biosciences 2011-12, Vol.36 (5), p.879-885
Main Authors: Song, Jin-Hui, Sun, Dong-Xue, Chen, Bin, Ji, Dai-Hong, Pu, Jie, Xu, Jie, Tian, Feng-De, Guo, Lin
Format: Article
Language:English
Subjects:
anticarcinogenic activity
Antineoplastic Agents, Phytogenic - pharmacology
Aryl Hydrocarbon Hydroxylases - antagonists & inhibitors
Biomedical and Life Sciences
Biomedicine
Cell Biology
cytochrome P-450
Cytochrome P-450 CYP2C9
Cytochrome P-450 CYP3A
Cytochrome P-450 CYP3A Inhibitors
Enzyme Assays
Enzymes
Humans
inhibitory concentration 50
Kinetics
Life Sciences
Liver
metabolism
Microbiology
Microsomes, Liver - drug effects
neoplasms
Pharmacology
Plant Sciences
Podophyllotoxin - pharmacology
Side effects
Toxins
Zoology
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0250-5991
0973-7138
DOI:10.1007/s12038-011-9143-9