Lawson Health Research Institute, London Health Sciences Centre, Western University, London, Ontario, Canada.
Department of Medicine, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada.
Pharmacol Res Perspect. 2017 Oct;5(5). doi: 10.1002/prp2.346.
Grapefruit can augment oral medication bioavailability through irreversible (mechanism-based) inhibition of intestinal CYP3A4. Supplementary data from our recent coffee-drug interaction clinical study showed some subjects had higher area under the plasma drug concentration - time curve (AUC) and plasma peak drug concentration (Cmax) of the CYP3A4 probe felodipine compared to aqueous control. It was hypothesized that coffee might interact like grapefruit in responsive individuals. Beans from six geographical locations were consistently brewed into coffee that was separated chromatographically to a methanolic fraction for in vitro inhibition testing of CYP3A4 metabolism of felodipine at 1% coffee strength. The effect of simultaneous incubation and 10-min preincubation with coffee fractions determined whether coffee had direct and mechanism-based inhibitory activity. A subsequent five-way randomized balanced controlled crossover clinical study evaluated the clinical pharmacokinetic interaction with single-dose felodipine. Grapefruit juice, water, or three of the in vitro tested coffees were ingested at 300 mL alone 1 h before and then with felodipine. In vitro, all six coffees decreased felodipine metabolism for both simultaneous and preincubation exposure compared to corresponding control. Five coffees demonstrated mechanism-based inhibition. Grapefruit increased felodipine AUC (25 vs. 13 ng.h/mL, P < 0.001) and Cmax (5.8 vs. 2.7 ng/mL, P < 0.001) and decreased dehydrofelodipine/felodipine AUC ratio (0.84 vs. 1.29, P < 0.001), while the three coffees caused no change in these parameters compared to water. Despite high in vitro potency of CYP3A4 inhibition, the coffees did not cause a clinical pharmacokinetic interaction possibly from insufficient amount of inhibitor(s) in coffee reaching intestinal CYP3A4 during the absorption phase of felodipine. The results of this study highlight the need for follow-up clinical testing when in vitro results indicate the possibility of an interaction.
葡萄柚可通过不可逆（基于机制）抑制肠道 CYP3A4 来增加口服药物的生物利用度。我们最近的咖啡-药物相互作用临床研究的补充数据显示，与水对照相比，一些受试者的 CYP3A4 探针非洛地平的血浆药物浓度-时间曲线下面积（AUC）和血浆峰药物浓度（Cmax）更高。据推测，咖啡可能会在有反应的个体中产生类似葡萄柚的相互作用。来自六个地理位置的咖啡豆被一致地冲泡成咖啡，然后通过色谱分离成甲醇部分，用于 1%咖啡强度下非洛地平 CYP3A4 代谢的体外抑制测试。同时孵育和 10 分钟预孵育与咖啡部分的效果决定了咖啡是否具有直接和基于机制的抑制活性。随后进行了一项五向随机平衡对照交叉临床研究，评估了单次剂量非洛地平的临床药代动力学相互作用。单独摄入 300 毫升葡萄柚汁、水或三种经体外测试的咖啡 1 小时前，然后与非洛地平一起摄入。体外，与相应对照相比，所有六种咖啡均降低了非洛地平的代谢，无论是同时暴露还是预孵育。五种咖啡显示出基于机制的抑制作用。葡萄柚增加了非洛地平的 AUC（25 比 13ng.h/mL，P<0.001）和 Cmax（5.8 比 2.7ng/mL，P<0.001），并降低了去氢非洛地平/非洛地平 AUC 比值（0.84 比 1.29，P<0.001），而三种咖啡与水相比，这些参数没有变化。尽管 CYP3A4 抑制的体外效力很高，但咖啡在非洛地平吸收阶段并没有引起临床药代动力学相互作用，可能是因为到达肠道 CYP3A4 的抑制剂（s）数量不足。这项研究的结果强调了当体外结果表明存在相互作用的可能性时，需要进行后续的临床测试。
