Inhibitory Effect of Apigenin on Losartan Metabolism and CYP2C9 Activity in vitro

Abstract

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.

The Effects of CYP2C19 genotype on the susceptibility for nephrosis in cardio-cerebral vascular disease treated by anticoagulation

“…CYP2C19 wild type is the fastest metabolism type in all of CYP2C19 genotype. [ 25 ] The ultrafast drug metabolism forces to increase dosages, which result in kidney toxicity and nephropathy. Hence, the use of the prodrug and tailored drug to protect against nephropathy is necessary.…”

A review of recent progress in improving the bioavailability of nutraceutical‐loaded emulsions after oral intake

“…After 4 weeks of feeding with a diet containing 3% green tea polyphenols, the expression and metabolic activity of hepatic CYP3A in mice decreased, resulting in an elevated plasma level of a CYP3A substrate drug, triazolam (Ikarashi et al., 2016). Apigenin has been shown to exhibit a competitive inhibitory effect on human CYP2C9 in liver microsomes and to reduce losartan metabolism in vitro (Wang et al., 2016). In vitro studies have shown that soy isoflavones, such as genistein and daidzein, were able to inhibit the activities of most human liver microsomal cytochromes P450 (except CYP2A6 and CYP2B6) by a noncompetitive mechanism (Kopecna‐Zapletalova et al., 2017).…”