Graduate College, Tianjin University of Traditional Chinese Medicine, Tianjin, China.
Pharmaceutical College, Tianjin Medical University, Tianjin, China.
AAPS PharmSciTech. 2019 Jul 8;20(6):247. doi: 10.1208/s12249-019-1444-6.
We aim to describe the influence of principal ingredients of Wuzhi capsule, schisandrin A (SIA) and schisantherin A (STA), on the pharmacokinetics of cyclosporin A (CsA) and to quantify the herb-drug interactions (HDIs) between SIA, STA, and CsA. CsA is a first-line immunosuppressant for anti-rejection therapy after solid organ transplantation, while narrow therapeutic window associated with strong hepatotoxicity largely limited its use. Wuzhi capsule, a liver-protective drug, was approved for coadministration with CsA to reduce the hepatotoxicity. There are few studies exploring HDIs of CsA when coadministered with Wuzhi capsule. The essential adjusted physicochemical data and pharmacokinetic parameters of SIA, STA, and CsA were collected. Then physiologically based pharmacokinetic (PBPK) models of SIA, STA, and CsA were built and verified in healthy subjects using Simcyp respectively. The refined PBPK models were used to estimate potential HDIs between CsA and SIA, STA. The simulated plasma concentration-time curves of CsA, SIA, and STA were in good accordance with the observed profiles respectively. CsA pharmacokinetics were improved after coadministration. After a single dose and multiple doses, the area under the plasma concentration-time curve (AUC) of CsA was increased by 47% and 226% when coadministered with STA, respectively, and by 8% and 36% when coadministered with SIA, respectively. PBPK models sufficiently described the pharmacokinetics of CsA, SIA, and STA. Compared with SIA, STA inhibited CsA metabolism to a greater extent. Our result revealed the dose of CsA can be reduced to maintain similar profile when used concomitantly with Wuzhi capsule.
我们旨在描述五味子胶囊的主要成分五味子甲素（SIA）和五味子醇甲（STA）对环孢素 A（CsA）药代动力学的影响，并定量分析 SIA、STA 和 CsA 之间的草药-药物相互作用（HDIs）。CsA 是实体器官移植后抗排斥治疗的一线免疫抑制剂，但其治疗窗较窄，且具有较强的肝毒性，在很大程度上限制了其应用。五味子胶囊是一种保肝药物，被批准与 CsA 联合使用以降低肝毒性。目前，关于 CsA 与五味子胶囊联合使用时发生 HDIs 的研究较少。本研究收集了 SIA、STA 和 CsA 的基本调整理化数据和药代动力学参数。然后，分别使用 Simcyp 建立和验证了 SIA、STA 和 CsA 的基于生理的药代动力学（PBPK）模型。使用精制的 PBPK 模型来估计 CsA 与 SIA、STA 之间潜在的 HDIs。CsA、SIA 和 STA 的模拟血浆浓度-时间曲线与观察到的曲线吻合良好。与单独给药相比，联合给药后 CsA 的药代动力学得到改善。单剂量和多剂量给药后，与 STA 联合给药时 CsA 的 AUC 分别增加了 47%和 226%，与 SIA 联合给药时分别增加了 8%和 36%。PBPK 模型充分描述了 CsA、SIA 和 STA 的药代动力学。与 SIA 相比，STA 更能抑制 CsA 的代谢。我们的研究结果表明，当与五味子胶囊同时使用时，可以减少 CsA 的剂量以维持相似的药代动力学特征。
