Division of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Keio University, 1-5-30, Shibakoen Minato-ku, Tokyo, 105-8512, Japan.
Division of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Keio University, 1-5-30, Shibakoen Minato-ku, Tokyo, 105-8512, Japan.
Drug Metab Pharmacokinet. 2019 Jun;34(3):181-186. doi: 10.1016/j.dmpk.2019.02.002. Epub 2019 Mar 6.
It has been suggested that the fruit components resveratrol (RSV), 6', 7'-dihydroxybergamottin (DHB), and bergamottin (BG) might inhibit cytochrome P450 2C19 (CYP2C19) activity, but the mode and potency of such inhibition are yet to be investigated. This study aimed to investigate the mode and kinetics of the inhibition of CYP2C19-based omeprazole metabolism by RSV or grapefruit juice components (DHB or BG). RSV and DHB reduced CYP2C19 activity in a preincubation time-dependent manner, suggesting that they inactivated CYP2C19 via mechanism-based inhibition (MBI). Although BG inactivated CYP2C19 in a preincubation time- and concentration-dependent manner, suggesting that both MBI and reversible inhibition contributed to these effects, the concentration required to achieve 50% inhibition was 26-fold higher for reversible inhibition than for MBI (0.859 and 0.0331 μM, respectively), indicating that the inhibition of CYP2C19 by BG is primarily attributable to MBI. Based on the estimated intestinal concentrations of these components, it is considered that >90% of CYP2C19 would be inactivated after the consumption of normal amounts of grapefruit juice or RSV-containing substances. In conclusion, these findings suggest that food containing these components has the potential to evoke drug-food interactions caused by the MBI of intestinal CYP2C19 activity in the clinical setting.
有人提出，水果成分白藜芦醇（RSV）、6'，7'-二羟基佛手柑素（DHB）和佛手柑素（BG）可能抑制细胞色素 P450 2C19（CYP2C19）活性，但这种抑制的模式和效力尚未得到研究。本研究旨在研究 RSV 或葡萄柚汁成分（DHB 或 BG）对基于 CYP2C19 的奥美拉唑代谢的抑制模式和动力学。RSV 和 DHB 以预孵育时间依赖性方式降低 CYP2C19 活性，表明它们通过机制基础抑制（MBI）使 CYP2C19 失活。尽管 BG 以预孵育时间和浓度依赖性方式使 CYP2C19 失活，表明 MBI 和可逆抑制均导致这些效应，但达到 50%抑制所需的浓度对于可逆抑制是 MBI 的 26 倍（分别为 0.859 和 0.0331 μM），表明 BG 对 CYP2C19 的抑制主要归因于 MBI。基于这些成分的肠道估计浓度，认为在正常食用葡萄柚汁或含有 RSV 的物质后，超过 90%的 CYP2C19 将失活。总之，这些发现表明，含有这些成分的食物有可能在临床环境中引起肠道 CYP2C19 活性的 MBI 引起的药物-食物相互作用。
