Background

This study investigates the interactions between various doses of hyperforin, a key compound in St. John’s Wort, and sedative hypnotics such as zolpidem, alprazolam, and midazolam. Since St John’s Wort is known to be an inducer of cytochrome P450 (CYP) 3A4, co-administration with drugs metabolized by CYP3A4 has been contraindicated.

Objective

We studied the risks of combination use and the possibility of safe combination by simulating the interaction of hyperforin, a key compound in St. John’s Wort, with drugs metabolized by CYP3A4 that can be used to relieve various symptoms of depression. Understanding these interactions is crucial for optimizing the treatment of depression and associated symptoms.

Results

The hyperforin physiologically based pharmacokinetic (PBPK) model was validated against clinical data, and PBPK models for zolpidem, alprazolam, and midazolam were used to predict herb–drug interactions. The simulations with a two-week co-administration scenario showed that hyperforin potentially acts as a weak inducer (hyperforin dose 2–20 mg, 3 times a day, AUC ratio 0.8–0.68) of 10 mg zolpidem metabolism, with sex-dependent interactions largely unaffected. However, the pharmacokinetics of alprazolam at doses of 0.25, 0.5, and 1 mg were minimally impacted (hyperforin dose 1–20 mg, 3 times a day, AUC ratio 0.96–0.87). In the case of 7.5 mg midazolam, hyperforin acted as a moderate to strong inducer (hyperforin dose 1–20 mg, 3 times a day, AUC ratio 0.26–0.20), even at low doses.

Conclusions

These findings emphasize the importance of careful monitoring and dose adjustments when using hyperforin and sedative hypnotics together. This study provided insights into co-administration of hyperforin and sedative hypnotics, facilitating the safe and effective use of these medications. Based on these results, it is necessary to know the possibility of safer drug combination, and to conduct clinical research and verification on this.

中文翻译：

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使用基于生理学的药代动力学模型预测金丝桃素和镇静催眠药（唑吡坦、阿普唑仑和咪达唑仑）之间的草药-药物相互作用

背景

本研究调查了不同剂量的金丝桃素（圣约翰草中的一种关键化合物）与镇静催眠药（如唑吡坦、阿普唑仑和咪达唑仑）之间的相互作用。由于圣约翰草已知是细胞色素 P450 (CYP) 3A4 的诱导剂，因此禁止与 CYP3A4 代谢的药物共同给药。

客观的

我们通过模拟金丝桃素（圣约翰草中的一种关键化合物）与 CYP3A4 代谢的可用于缓解各种抑郁症状的药物的相互作用，研究了联合使用的风险和安全联合的可能性。了解这些相互作用对于优化抑郁症及相关症状的治疗至关重要。

结果

金丝桃素基于生理学的药代动力学 (PBPK) 模型根据临床数据进行了验证，唑吡坦、阿普唑仑和咪达唑仑的 PBPK 模型用于预测草药与药物的相互作用。两周联合给药方案的模拟表明，金丝桃素可能作为 10 mg 唑吡坦代谢的弱诱导剂（金丝桃素剂量 2-20 mg，每天 3 次，AUC 比率 0.8-0.68），具有性别依赖性相互作用基本上不受影响。然而，0.25、0.5 和 1 mg 剂量的阿普唑仑的药代动力学受到的影响很小（金丝桃素剂量 1-20 mg，每天 3 次，AUC 比率 0.96-0.87）。在 7.5 mg 咪达唑仑的情况下，金丝桃素可作为中度至强诱导剂（金丝桃素剂量 1-20 mg，每天 3 次，AUC 比率 0.26-0.20），即使在低剂量时也是如此。

结论

这些发现强调了同时使用金丝桃素和镇静催眠药时仔细监测和剂量调整的重要性。这项研究为金丝桃素和镇静催眠药的联合用药提供了见解，促进了这些药物的安全有效使用。基于这些结果，有必要了解更安全的药物组合的可能性，并对此进行临床研究和验证。