Inhibitory Effect of Apigenin on Losartan Metabolism and CYP2C9 Activity in vitro.
BACKGROUND
CYP2C9 is one of the most important phase I drug-metabolizing enzymes in liver. The objective of this work was to investigate the effects of apigenin on the metabolism of losartan and human CYP2C9 and rat CYP2C11 activity in vitro.


METHODS
Different concentrations of apigenin were added to a 100 mmol/l Tris-HCl reaction mixture containing 2 pmol/ml recombinant human CYP2C9.1, 0.25 mg/ml human liver microsomes or 0.5 mg/ml rat liver microsomes to determine the half maximal inhibition or a half-maximal inhibitory concentration (IC50) on the metabolism of losartan. In addition, diclofenac used as CYP2C9 substrate was performed to determine the effects of apigenin on CYP2C9.


RESULTS
The results showed that apigenin has the inhibitory effect on the metabolism of losartan in vitro, the IC50 was 7.61, 4.10 and 11.07 μmol/l on recombinant CYP2C9 microsomes, human liver microsomes and rat liver microsomes, respectively. Meanwhile, apigenin's mode of action on human CYP2C9 activity was competitive for the substrate diclofenac. In contrast to its potent inhibition of CYP2C9 in humans (9.51 μmol/l), apigenin had lesser effects on CYP2C11 in rat (IC50 = 15.51 μmol/l).


CONCLUSIONS
The observations imply that apigenin has the inhibitory effect on the metabolism of losartan and CYP2C9 activity in vitro. More attention should be paid as to when losartan should be administrated combined with apigenin.
Department of Pharmacy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.
Zhe
Z
Wang
Yun
Y
Gong
Da-Li
DL
Zeng
Lian-Guo
LG
Chen
Gao-Tong
GT
Lin
Cheng-Ke
CK
Huang
Wei
W
Sun
Meng-Chun
MC
Chen
Guo-Xin
GX
Hu
Rui-Jie
RJ
Chen
D000818:Animals; D047310:Apigenin / Q000378:metabolism* / Q000494:pharmacology*; D065729:Cytochrome P-450 CYP2C9 / Q000378:metabolism*; D065688:Cytochrome P-450 CYP2C9 Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D019808:Losartan / Q000378:metabolism* / Q000494:pharmacology*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D051381:Rats; D017207:Rats, Sprague-Dawley
D065688:Cytochrome P-450 CYP2C9 Inhibitors; D004791:Enzyme Inhibitors; D047310:Apigenin; D065729:Cytochrome P-450 CYP2C9; D019808:Losartan