title: Inhibition of CYP3A4 and CYP2C9 by podophyllotoxin: implication for clinical drug-drug interactions.
abstract: 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 meu M 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 meu M, respectively. Additionally, PPT exerted time-dependent inhibition towards CYP3A4 and the kinetic parameters were 4.4+/- 2.1 meu M 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.
authors: Orthopedics Department 2, Affiliated Zhongshan Hospital of Dalian University, Dalian 116 001, China.
authors: Jin-Hui
authors: JH
authors: Song
authors: Dong-Xue
authors: DX
authors: Sun
authors: Bin
authors: B
authors: Chen
authors: Dai-Hong
authors: DH
authors: Ji
authors: Jie
authors: J
authors: Pu
authors: Jie
authors: J
authors: Xu
authors: Feng-De
authors: FD
authors: Tian
authors: Lin
authors: L
authors: Guo
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors*; D065729:Cytochrome P-450 CYP2C9; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D057075:Enzyme Assays; D006801:Humans; D007700:Kinetics; D008862:Microsomes, Liver / Q000187:drug effects*; D011034:Podophyllotoxin / Q000494:pharmacology*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D065692:Cytochrome P-450 CYP3A Inhibitors; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D011034:Podophyllotoxin