Li Xiangyu, Hu Xiaoxia, Yang Fang, Hu Guoxin, Yuan Lingjing, Li Junwei
Department of Pharmacy, Shaoxing Keqiao Women & Children's Hospital, Shaoxing, Zhejiang, China.
School of Pharmaceutical Sciences, School of Pharmacy of Wenzhou Medical University, Wenzhou, Zhejiang, China.
Biomed Chromatogr. 2025 Sep;39(9):e70184. doi: 10.1002/bmc.70184.
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), CYP2C91, 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 CYP2C91 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 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.
作为人类肝脏中主要的细胞色素（CYP）2C亚型，CYP2C9介导缬沙坦（一种广泛应用的血管紧张素受体阻滞剂）的氧化代谢。尽管有大量证据表明黄酮类化合物会影响药物的药代动力学，但山奈酚对CYP2C9介导的缬沙坦代谢的具体抑制作用尚不清楚。在本研究中，对这种药代动力学关键相互作用进行了体外和体内的系统研究。通过大鼠肝微粒体（RLM）、CYP2C91和人肝微粒体（HLM）代谢系统在体外计算山奈酚对缬沙坦抑制的动力学参数（IC50和Ki值）。此外，将24只SD大鼠随机分为四组（单独给予缬沙坦（10 mg/kg）以及与山奈酚（3、6或10 mg/kg）联合给药），以专门通过灌胃研究体内相互作用。经尾静脉采血后，通过超高效液相色谱-串联质谱法测定样品中缬沙坦及其主要代谢产物4-羟基缬沙坦的浓度。山奈酚在RLM、HLM和CYP2C91系统中的IC50值分别为9.87、8.54和8.75 μM，Ki值为4.68 μM。山奈酚通过对CYP450的混合竞争性抑制对缬沙坦代谢表现出相对较强的抑制作用。此外，与SD大鼠对照组相比，联合给药组的AUC和C值（缬沙坦升高，4-羟基缬沙坦降低）有显著变化。山奈酚是一种与临床相关的CYP2C9抑制剂，可显著抑制缬沙坦代谢，联合给药时可能需要调整剂量。本研究强调了饮食中黄酮类化合物干扰心血管药物治疗的潜在风险尚未得到充分认识，这值得在人体试验中进行临床验证。
