Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, PR China.
Shandong Provincial Key Laboratory of Automotive Electronic Technology, Institute of Automation, Shandong Academy of Sciences, Jinan 250014, PR China.
J Ethnopharmacol. 2019 May 23;236:277-287. doi: 10.1016/j.jep.2018.07.008. Epub 2019 Feb 28.
Yuanhu Zhitong prescription (YZP) is a commonly used and relatively simple clinical herb preparation recorded in the China Pharmacopoeia. It contains Corydalis yanhusuo (Chinese name, Yanhusuo [YH]) and Angelica dahurica (Hoffm.) (Chinese name, Baizhi [BZ]), and has a long history of use in traditional Chinese medicine (TCM) for the treatment of stomach pain, hypochondriac pain, headache, and dysmenorrhea.
A TCM-ADMEpred method is developed for novel strategy for poly-pharmacokinetics prediction of TCM. To predict the pharmacokinetic characteristics of the main YZP constituents in rat plasma using in silico models, based on the theory that structurally similar constituents show similar pharmacokinetic properties. This approach may facilitate in silico prediction of the pharmacokinetics of TCM.
A robust platform using ultra-performance liquid chromatography coupled with triple quadrupole electrospray tandem mass spectrometry (UPLC-ESI-MS/MS) was developed and validated for simultaneous determination of seven active YZP constituents in rat plasma. These seven compounds were divided into two structural classes, alkaloids and coumarins. The correlation between AUC profiles within a structural class was expressed as Γ, and this variable was used to develop two novel in silico models to predict constituent AUC values. The pharmacokinetics of tetrahydropalmatine, tetrahydroberberine, and corydaline following YZP administration were predicted using the Γ-values of α-allocryptopine observed following YH administration, while those of imperatorin and isoimperatorin following BZ administration were predicted using the Γ-values of byakangelicin observed following YZP administration.
The UPLC-ESI-MS/MS method was successfully used to evaluate pharmacokinetic parameters after oral YZP, YH, or BZ administration. Our findings showed that co-administration of YH and BZ increased the AUC of four alkaloid constituents and reduced the AUC of three coumarin constituents, which might provide a scientific rationale for co-administering these herbs clinically as a YZP preparation, thus increasing their efficacy and reducing toxicity. The AUC values of imperatorin and isoimperatorin were predicted 3 h after oral BZ administration, with the bias ratios between the theoretical values and the observed experimental values ranging from 0.61% to 11.4%, and average bias ratios of 5.8% and 8.0%, respectively. The AUC values of tetrahydropalmatine, tetrahydroberberine, and corydaline were predicted 3 h after oral YZP administration, with bias ratios ranging from 3.7% to 46.4%, and average bias ratios of 23.8%, 15.4%, and 25.8%, respectively.
The UPLC-ESI-MS/MS method was successfully applied to pharmacokinetic evaluations after oral administration of YZP, YH, and BZ to rats. The Γ variable was used to express the correlation between the AUC profiles of structurally similar compounds. This facilitated the development of an in silico model that was used to predict the AUC of three alkaloids in YZP and of two coumarins in BZ. Calculation of the bias ratios between the predicted and experimental values suggested that this in silico model provided a viable approach for the prediction of TCM pharmacokinetics.
元胡止痛方（YZP）是中国药典中记录的一种常用且相对简单的临床草药制剂。它由延胡索（中国名：延胡索[YH]）和白芷（Hoffm.）（中国名：白芷[BZ]）组成，在中医药（TCM）中已有治疗胃痛、腹痛、头痛和痛经的悠久历史。
开发一种 TCM-ADMEpred 方法，为 TCM 的多药代动力学预测提供新策略。基于结构相似的成分表现出相似的药代动力学特性的理论，使用基于计算的模型预测 YZP 主要成分在大鼠血浆中的药代动力学特征。这种方法可能有助于 TCM 的药代动力学的计算机预测。
使用超高效液相色谱-三重四极杆电喷雾串联质谱法（UPLC-ESI-MS/MS）建立并验证了一种强大的平台，用于同时测定大鼠血浆中 7 种活性 YZP 成分。这 7 种化合物分为两类，生物碱和香豆素。结构类别内 AUC 谱之间的相关性表示为 Γ，该变量用于开发两种新的计算模型，以预测成分 AUC 值。YZP 给药后，使用观察到的 YH 给药后 α-allocryptopine 的 Γ 值预测四氢巴马汀、四氢小檗碱和延胡索碱的 AUC 值，而 BZ 给药后预测异欧前胡素和欧前胡素的 AUC 值使用观察到的 YZP 给药后 byakangelicin 的 Γ 值。
成功地使用 UPLC-ESI-MS/MS 方法评估了 YZP、YH 或 BZ 口服后的药代动力学参数。我们的研究结果表明，YH 和 BZ 联合给药增加了 4 种生物碱成分的 AUC，降低了 3 种香豆素成分的 AUC，这可能为临床联合使用这些草药作为 YZP 制剂提供科学依据，从而提高疗效，降低毒性。YZP 给药后 3 小时预测了异欧前胡素和欧前胡素的 AUC 值，理论值与实验观察值之间的偏差比范围为 0.61%至 11.4%，平均偏差比分别为 5.8%和 8.0%。YZP 给药后 3 小时预测了四氢巴马汀、四氢小檗碱和延胡索碱的 AUC 值，偏差比范围为 3.7%至 46.4%，平均偏差比分别为 23.8%、15.4%和 25.8%。
成功地应用 UPLC-ESI-MS/MS 方法对大鼠口服 YZP、YH 和 BZ 后的药代动力学进行了评价。Γ 变量用于表示结构相似化合物 AUC 谱之间的相关性。这有助于开发一种计算模型，用于预测 YZP 中的 3 种生物碱和 BZ 中的 2 种香豆素的 AUC。计算预测值与实验值之间的偏差比表明，这种计算模型为 TCM 药代动力学的预测提供了一种可行的方法。
