The Effect of Kaempferol on Valsartan Metabolism In Vitro and In Vivo and the Underlying Mechanism With Cytochrome p450 Using UPLC‐MS/MS

ABSTRACT As the predominant cytochrome (CYP) 2C isoform in the human liver, CYP2C9 mediates the oxidative metabolism of valsartan, a widely prescribed angiotensin receptor blocker. Despite extensive evidence that flavonoids can affect drug pharmacokinetics, the specific inhibitory effect of kaempferol on CYP2C9‐mediated valsartan metabolism is unknown. In this study, this pharmacokinetically critical interaction was systematically investigated in vitro and in vivo. The kinetics of kaempferol inhibition of valsartan (IC50 and Ki values) were calculated in vitro via rat liver microsome (RLM), CYP2C9*1, and human liver microsome (HLM) metabolic systems. Additionally, 24 SD rats were randomly divided into four groups (valsartan alone (10 mg/kg) and coadministration with kaempferol (3, 6, or 10 mg/kg)) to study the interactions in vivo via oral gavage specifically. After blood collection via the tail vein, the concentrations of valsartan and its major metabolite, 4‐OH valsartan, in the samples were determined via UPLC–MS/MS. The IC50 values of kaempferol in the RLM, HLM, and CYP2C9*1 systems were 9.87, 8.54, and 8.75 μM, respectively, and the Ki value was 4.68 μM. Kaempferol exhibited relatively strong inhibition of valsartan metabolism via mixed competitive inhibition of CYP450. Moreover, the AUC and C max values in the coadministration groups increased (valsartan) or decreased (4‐OH valsartan) significantly compared with those of the control group in SD rats. Kaempferol is a clinically relevant CYP2C9 inhibitor that significantly inhibits valsartan metabolism, potentially necessitating dose adjustments during coadministration. This study highlights the underappreciated risks of dietary flavonoid interference with cardiovascular pharmacotherapy, which warrants clinical validation in human trials.