Hongbing Zhang1, Xin Wu2, Jun Xu1, Suxiao Gong1, Yanqi Han1, Tiejun Zhang3, Changxiao Liu4. 1. State Key Laboratory of Drug Delivery Technology and Pharmacokinetics, Tianjin Institute of Pharmaceutical Research, Tianjin 300193, China. 2. School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China. 3. State Key Laboratory of Drug Delivery Technology and Pharmacokinetics, Tianjin Institute of Pharmaceutical Research, Tianjin 300193, China. Electronic address: zhangtj@tjipr.com. 4. State Key Laboratory of Drug Delivery Technology and Pharmacokinetics, Tianjin Institute of Pharmaceutical Research, Tianjin 300193, China. Electronic address: liuchangxiao@163.com.
Abstract
BACKGROUND: According to the compatibility theory, therapeutic effects of Chinese medicine prescription are generally attributed to the synergism of multi-herbs. Quality-markers, as the crucial effective components, play a key role in the interaction of compatibility. Pharmacokinetic studies could illustrate the interaction between multiple components in dynamics perspective. PURPOSE: This study aims to establish a rapid, reliable and sensitive ultra performance liquid chromatography coupled with tandem mass spectrometry method for simultaneous determination of corydaline, tetrahydropalmatine, protopine, imperatorin and isoimperatorin (quality-markers of Yuanhu Zhitong prescription) in rat plasma, and then applied to the comparative pharmacokinetic study for clearing the interaction of compatibility in Yuanhu Zhitong prescription. METHODS: Five quality-markers were separated on a Waters Acquity UPLC BEH C18 column (2.1 mm × 50 mm, 1.7 µm) by gradient elution with 0.1% formic acid-water and 0.1% formic acid-acetonitrile. Detection was performed in the positive ionization and multiple reaction monitoring mode. The analytical method was validated and successfully applied to the comparative pharmacokinetic study after oral administration of Yuanhu Zhitong prescription and single-herb extracts. RESULTS: Calibration curves showed good linearity over the concentration ranges of 0.25-500 ng/ml for corydaline, tetrahydropalmatine and isoimperatorin, 0.1-200 ng/ml for protopine, and 0.5-500 ng/ml for imperatorin, respectively. Compared with Rhizoma corydalis group, AUC0-t and AUC0-∞ significantly increased (p < 0.01 for corydaline and tetrahydropalmatine, and p < 0.05 for protopine) after oral administration of Yuanhu Zhitong prescription extract. Meanwhile, Cmax of corydaline and tetrahydropalmatine increased remarkably, from 93.00 µg/l to 196.35 µg/l for corydaline (p < 0.05) and 181.62 µg/l to 311.22 µg/l for tetrahydropalmatine (p < 0.01). In addition, MRT0-t and MRT0-∞ of corydaline, as well as Tmax of protopine in Yuanhu Zhitong prescription group were obviously delayed compared to Rhizoma corydalis group (p < 0.01). CONCLUSION: These achieved results indicated that the compatibility of Rhizoma corydalis and Radix Angelicae dahuricae lead to greater absorption of corydaline, tetrahydropalmatine and protopine, which would be help to better understand the compatibility mechanism of Yuanhu Zhitong prescription.
BACKGROUND: According to the compatibility theory, therapeutic effects of Chinese medicine prescription are generally attributed to the synergism of multi-herbs. Quality-markers, as the crucial effective components, play a key role in the interaction of compatibility. Pharmacokinetic studies could illustrate the interaction between multiple components in dynamics perspective. PURPOSE: This study aims to establish a rapid, reliable and sensitive ultra performance liquid chromatography coupled with tandem mass spectrometry method for simultaneous determination of corydaline, tetrahydropalmatine, protopine, imperatorin and isoimperatorin (quality-markers of Yuanhu Zhitong prescription) in rat plasma, and then applied to the comparative pharmacokinetic study for clearing the interaction of compatibility in Yuanhu Zhitong prescription. METHODS: Five quality-markers were separated on a Waters Acquity UPLC BEH C18 column (2.1 mm × 50 mm, 1.7 µm) by gradient elution with 0.1% formic acid-water and 0.1% formic acid-acetonitrile. Detection was performed in the positive ionization and multiple reaction monitoring mode. The analytical method was validated and successfully applied to the comparative pharmacokinetic study after oral administration of Yuanhu Zhitong prescription and single-herb extracts. RESULTS: Calibration curves showed good linearity over the concentration ranges of 0.25-500 ng/ml for corydaline, tetrahydropalmatine and isoimperatorin, 0.1-200 ng/ml for protopine, and 0.5-500 ng/ml for imperatorin, respectively. Compared with Rhizoma corydalis group, AUC0-t and AUC0-∞ significantly increased (p < 0.01 for corydaline and tetrahydropalmatine, and p < 0.05 for protopine) after oral administration of Yuanhu Zhitong prescription extract. Meanwhile, Cmax of corydaline and tetrahydropalmatine increased remarkably, from 93.00 µg/l to 196.35 µg/l for corydaline (p < 0.05) and 181.62 µg/l to 311.22 µg/l for tetrahydropalmatine (p < 0.01). In addition, MRT0-t and MRT0-∞ of corydaline, as well as Tmax of protopine in Yuanhu Zhitong prescription group were obviously delayed compared to Rhizoma corydalis group (p < 0.01). CONCLUSION: These achieved results indicated that the compatibility of Rhizoma corydalis and Radix Angelicae dahuricae lead to greater absorption of corydaline, tetrahydropalmatine and protopine, which would be help to better understand the compatibility mechanism of Yuanhu Zhitong prescription.