Influence of St. John’s Wort on Intravenous Fentanyl Pharmacokinetics, Pharmacodynamics, and Clinical Effects
Influence of St. John’s Wort on Intravenous Fentanyl Pharmacokinetics, Pharmacodynamics, and Clinical Effects
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圣约翰草对静脉注射芬太尼药代动力学、药效学和临床效果的影响
作者：
Michael J. Loughren;Evan D. Kharasch;Megan C. Kelton;Karen L. Syrjala;Danny D. Shen
背景：患者经常使用补充和替代草药，因此存在潜在的不良草药相互作用。芬太尼由肝脏 CYP3A4 代谢，并被认为由血脑屏障 P-糖蛋白转运。这两种处置过程都可以通过草药圣约翰草来调节。这项研究评估了圣约翰草对固定剂量和表观稳态静脉注射芬太尼药代动力学、药效学和临床效果的影响。方法：在随机平行组设计中，健康志愿者在连续 30 天的圣约翰草（300 mg，每天三次；n = 8）或安慰剂对照（n = 8）之前和之后，分别接受芬太尼固定剂量输注和单独定制的目标控制输注。测量了芬太尼血浆浓度、瞳孔直径、对实验性疼痛（冷加压剂）的镇痛反应、主观副作用和认知影响。对血浆芬太尼浓度和瞳孔直径的变化进行药代动力学-药效学建模。结果：圣约翰草不会改变芬太尼的药代动力学。使用圣约翰草（分别为 1.13 ± 0.29 和 1.24 ± 0.26）或安慰剂（分别为 0.96 ± 0.28 和 1.12 ± 0.27）之前和之后的清除率（升/分钟）没有差异。根据固定剂量和定制芬太尼输注后瞳孔收缩测量，圣约翰草也不影响芬太尼药效学。圣约翰草前后的 EC50 (ng/ml) 分别为 1.1 ± 0.7 和 1.4 ± 0.9，而安慰剂前后分别为 1.2 ± 0.8 和 1.4 ± 1.7。圣约翰草前后的效应部位平衡时间 T½,ke0（分钟）分别为 12.8 ± 5.3 和 11.3 ± 6.4，而安慰剂前后分别为 11.4 ± 6.4 和 11.1 ± 5.6。圣约翰草对芬太尼的镇痛、认知表现或躯体认知情感作用没有影响。结论：圣约翰草不会改变芬太尼的药代动力学、药效学或临床效果，表明对肝脏清除率或血脑屏障流出没有影响。服用圣约翰草的患者对静脉注射芬太尼进行麻醉或镇痛的反应可能不会有不同。在圣约翰草治疗前后，对志愿者的药代动力学和药效学（瞳孔直径随时间变化）进行了检查。没有发现差异，表明这种草药不会影响芬太尼的临床行为。
Background: Patients often use complementary and alternative herbal medicines, hence, potential exists for adverse herb–drug interactions. Fentanyl is metabolized by hepatic CYP3A4 and considered transported by blood–brain barrier P-glycoprotein. Both disposition processes could be upregulated by the herbal St. John’s wort. This investigation evaluated effects of St. John’s wort on fixed-dose and apparent steady-state IV fentanyl pharmacokinetics, pharmacodynamics, and clinical effects. Methods: Healthy volunteers received a fentanyl fixed-dose infusion and an individually tailored target controlled infusion on separate days, before and after 30-day St. John’s wort (300 mg thrice daily; n = 8) or placebo control (n = 8) in a randomized parallel-group design. Fentanyl plasma concentrations, pupil diameter, analgesic response to experimental pain (cold pressor), subjective side effects, and cognitive effects were measured. Plasma fentanyl concentrations and changes in pupil diameter were subjected to pharmacokinetic–pharmacodynamic modeling. Results: St. John’s wort did not alter fentanyl pharmacokinetics. Clearance (l/min) before and after St. John’s wort (1.13 ± 0.29 and 1.24 ± 0.26, respectively) or placebo (0.96 ± 0.28 and 1.12 ± 0.27, respectively) were not different. St. John’s wort also did not affect fentanyl pharmacodynamics as measured by pupil constriction after fixed-dose and tailored fentanyl infusions. EC50 (ng/ml) was 1.1 ± 0.7 and 1.4 ± 0.9 before and after St. John’s wort versus 1.2 ± 0.8 and 1.4 ± 1.7 before and after placebo. Effect site equilibration time, T½,ke0 (min), was 12.8 ± 5.3 and 11.3 ± 6.4 before and after St. John’s wort versus 11.4 ± 6.4 and 11.1 ± 5.6 before and after placebo. St. John’s wort had no influence on analgesia, cognitive performance, or somatic cognitive–affective effects of fentanyl. Conclusions: St. John’s wort did not alter fentanyl pharmacokinetics, pharmacodynamics or clinical effects, suggesting no effect on hepatic clearance or blood-brain barrier efflux. Patients taking St. John’s wort will likely not respond differently to IV fentanyl for anesthesia or analgesia. The pharmacokinetics and pharmacodynamics (pupillary diameter over time) were examined in volunteers before and after treatment with St. John’s wort. No differences were seen, suggesting that this herbal medication does not influence the clinical behavior of fentanyl.
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影响因子：
120.7
作者：
Edinger, JD;Wohlgemuth, WK;Quillian, RE
通讯作者：
Quillian, RE
阿米替林和萘普生治疗纤维肌痛患者的随机对照试验。
影响因子：
--
作者：
Goldenberg,DL;Felson,DT;Dinerman,H
通讯作者：
Dinerman,H
通过血脑屏障主动转运芬太尼。
DOI：
--
发表时间：
1999
期刊：
The Journal of pharmacology and experimental therapeutics
影响因子：
--
作者：
Henthorn,TK;Liu,Y;Mahapatro,M;Ng,KY
通讯作者：
Ng,KY
影响因子：
3.8
作者：
Lamba, V;Yasuda, K;Schuetz, EG
通讯作者：
Schuetz, EG