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).

CONCLUSION

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.