URL Pharma, Inc, Philadelphia, Pennsylvania, USA.
Clin Ther. 2012 Oct;34(10):2161-73. doi: 10.1016/j.clinthera.2012.08.007. Epub 2012 Aug 31.
The labeling for colchicine (indicated for acute gout flares or prophylaxis) includes strict advisories regarding drug-drug and drug-food interactions, including warnings against consuming grapefruit or grapefruit juice during treatment. Two of the furocoumarins in grapefruit juice and Seville orange juice can inhibit intestinal cytochrome P450 (CYP) isozyme 3A4 and P-glycoprotein (involved in colchicine metabolism and transport). Severe toxicities in patients consuming these juices while taking other drugs metabolized through these pathways have been reported.
Two Phase I studies assessed the effects of multiple daily consumptions of Seville orange juice or grapefruit juice on the pharmacokinetic properties of colchicine in healthy volunteers.
Healthy volunteers were enrolled in 2 open-label, Phase I studies. Undiluted juice (240 mL) was administered twice daily for 4 days. Pharmacokinetic data were obtained following a single 0.6-mg dose of colchicine before the administration of juice and again following a single 0.6-mg dose of colchicine on the final day of juice administration. In each study, blood samples for pharmacokinetics were collected before dosing with colchicine and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours postdose. All subjects were monitored for adverse events (AEs) throughout the confinement portion of the study and were queried at the outpatient visits. AEs were coded according to corresponding MedDRA-coded system organ classes.
Forty-four subjects received either grapefruit juice (72.7% male; 90.9% white) or Seville orange juice (62.5% female; 100% white). Although it is considered to be a moderate concentration-dependent CYP3A4 inhibitor, grapefruit juice did not significantly affect the pharmacokinetic parameters of colchicine. When colchicine was administered with Seville orange juice, a moderate inhibitor, C(max) and AUC were decreased by ∼24% and ∼20%, respectively. Seville orange juice also caused, on average, a 1-hour delay in T(max). Colchicine in combination with grapefruit or Seville orange juice was well tolerated. There were no significant treatment-related AEs reported, and the most likely AEs were general gastrointestinal events.
In contrast to label warnings based on the literature, grapefruit juice did not affect the pharmacokinetics of colchicine. Seville orange juice paradoxically reduced absorption of colchicine and increased T(max), but the clinical significance of this is unknown. Contrary to the expected effects of inhibiting the enzymes that metabolize colchicine, neither juice increased exposure to colchicine. However, the absence of a positive control in these studies dictates that caution should be used when applying these results clinically. ClinicalTrials.gov identifiers: NCT00960193 and NCT00984009.
秋水仙碱（用于急性痛风发作或预防）的标签包括关于药物相互作用和药物-食物相互作用的严格建议，包括在治疗期间避免食用葡萄柚或葡萄柚汁的警告。葡萄柚和塞维利亚橙子汁中的两种呋喃香豆素可抑制肠道细胞色素 P450（CYP）同工酶 3A4 和 P-糖蛋白（参与秋水仙碱的代谢和转运）。有报道称，同时服用这些果汁和其他通过这些途径代谢的药物的患者会出现严重的毒性。
两项 I 期研究评估了多次每日饮用塞维利亚橙子汁或葡萄柚汁对健康志愿者秋水仙碱药代动力学特性的影响。
健康志愿者被纳入 2 项开放标签、I 期研究。在给予秋水仙碱前 4 天每天两次给予未稀释的果汁（240 毫升）。在给予果汁的最后一天再次给予秋水仙碱单剂量 0.6 毫克后，获得单次 0.6 毫克秋水仙碱的药代动力学数据。在每项研究中，在给予秋水仙碱前和给药后 0.5、1、1.5、2、3、4、5、6、8、12 和 24 小时采集血样进行药代动力学研究。所有受试者在研究的禁闭部分均进行不良事件（AE）监测，并在门诊就诊时进行询问。AE 根据相应的 MedDRA 编码系统器官类别进行编码。
44 名受试者接受了葡萄柚汁（72.7%为男性；90.9%为白人）或塞维利亚橙子汁（62.5%为女性；100%为白人）。尽管葡萄柚汁被认为是一种中等浓度依赖性 CYP3A4 抑制剂，但它并未显著影响秋水仙碱的药代动力学参数。当秋水仙碱与中等抑制剂塞维利亚橙子汁一起给药时，C(max)和 AUC 分别降低约 24%和 20%。塞维利亚橙子汁还平均导致 T(max)延迟 1 小时。秋水仙碱与葡萄柚汁或塞维利亚橙子汁联合使用耐受性良好。未报告与治疗相关的严重不良事件，最可能的不良事件是一般胃肠道事件。
与基于文献的标签警告相反，葡萄柚汁并未影响秋水仙碱的药代动力学。塞维利亚橙子汁反而是秋水仙碱的吸收减少，并增加了 T(max)，但这一临床意义尚不清楚。与预期抑制代谢秋水仙碱的酶的作用相反，两种果汁均未增加秋水仙碱的暴露量。然而，这些研究中缺乏阳性对照，因此在临床上应用这些结果时应谨慎。临床试验.gov 标识符：NCT00960193 和 NCT00984009。
