Abdelkawy Khaled S, Donia Ahmed M, Turner R Brigg, Elbarbry Fawzy
Faculty of Pharmacy, Kafrelsheikh University, Kafr el-Sheikh, Egypt.
Faculty of Pharmacy, Tanta University, Tanta, Egypt.
Drugs R D. 2016 Sep;16(3):271-278. doi: 10.1007/s40268-016-0140-1.
Several severe drug interactions have been reported when sildenafil, a potent drug for the treatment of erectile dysfunction, is co-administered with drugs or herbal remedies that inhibit cytochrome P450 (CYP) 3A4. This study evaluates the effects of two citrus fruit juices, lemon and Seville orange, on the pharmacokinetics of sildenafil in male healthy subjects following a single oral dose.
We conducted an open-label, three-way crossover study in nine healthy male volunteers. Participants received a single oral dose of sildenafil (50 mg) after pretreatment with 250 mL of either water (control), undiluted lemon juice, or Seville orange juice for 3 consecutive days. All subjects were monitored for adverse effects during the study period. Plasma samples were collected for 12 h after dosing and analyzed for sildenafil concentration.
Compared with pretreatment with water, Seville orange juice significantly increased the area under the plasma concentration-time curve from time zero to infinity and the peak plasma concentration of sildenafil by 44 % (90 % confidence interval [CI] 30-60) and 18 % (90 % CI 108-129), respectively, without affecting the time to reach peak plasma concentration. Additionally, Seville orange juice significantly reduced the apparent oral clearance of sildenafil by 30 % (90 % CI 63-75) without affecting its elimination half-life. In contrast, lemon juice did not cause any significant alterations in the pharmacokinetics of sildenafil. There was no significant treatment-related adverse effects reported during the study.
Although it is considered as a moderate CYP3A4 inhibitor, Seville orange only caused a mild increase in exposure to sildenafil after a single oral dose, without manifestation of any adverse effects. The enhanced bioavailability of sildenafil by Seville orange may be attributed to inhibition of its intestinal first-pass effect (CYP3A4 and or p-glycoprotein). Lemon juice, in contrast, had no effects on the pharmacokinetics of sildenafil.
有报道称，治疗勃起功能障碍的强效药物西地那非与抑制细胞色素P450（CYP）3A4的药物或草药联合使用时会发生几种严重的药物相互作用。本研究评估了两种柑橘类果汁（柠檬汁和酸橙汁）对健康男性受试者单次口服西地那非后药代动力学的影响。
我们对9名健康男性志愿者进行了一项开放标签、三交叉研究。参与者在连续3天每天预处理250毫升水（对照）、未稀释的柠檬汁或酸橙汁后，单次口服西地那非（50毫克）。在研究期间对所有受试者的不良反应进行监测。给药后12小时采集血浆样本，分析西地那非浓度。
与用水预处理相比，酸橙汁使西地那非从时间零点到无穷大的血浆浓度-时间曲线下面积和血浆峰浓度分别显著增加44%（90%置信区间[CI]30-60）和18%（90%CI 108-129），且不影响达到血浆峰浓度的时间。此外，酸橙汁使西地那非的表观口服清除率显著降低30%（90%CI 63-75），但不影响其消除半衰期。相比之下，柠檬汁对西地那非的药代动力学没有引起任何显著改变。研究期间未报告与治疗相关的显著不良反应。
尽管酸橙被认为是一种中度CYP3A4抑制剂，但单次口服后仅使西地那非的暴露量轻度增加，且未出现任何不良反应。酸橙提高西地那非的生物利用度可能归因于对其肠道首过效应（CYP3A4和/或P-糖蛋白）的抑制。相比之下，柠檬汁对西地那非的药代动力学没有影响。
