College of Pharmaceutical Sciences and Chinese Medicine, Southwest University, 2# Tiansheng Road, Beibei District, Chongqing 400715, China.
School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, 312# Anshanxi Road, Nankai District, Tianjin 300193, China.
Molecules. 2018 Apr 25;23(5):1004. doi: 10.3390/molecules23051004.
Radix , containing coumarins, which might affect cytochrome P450 enzyme (CYP450) activity, has been co-administered with ligustrazine, a substrate of CYP450s, for the clinical treatment of migraine. However, whether a pharmacokinetic-based synergy exists between Radix and ligustrazine is still unknown. In this study, the total coumarin extract (TCE) of Radix (50 mg/kg, orally) reinforced the anti-migraine activity of ligustrazine by declining head scratching, plasma calcitonin gene-related peptide, and serum nitric oxide, as well as increasing plasma endothelin levels in rats ( < 0.05). Moreover, the pharmacokinetic study reflected that TCE potentiated the area under the concentration⁻time curve of ligustrazine and prolonged its mean retention time in rats ( < 0.05). Besides, the IC for TCE, imperatorin and isoimperatorin inhibiting ligustrazine metabolism were 5.0 ± 1.02, 1.35 ± 0.46, 4.81 ± 1.14 µg/mL in human liver microsomes, and 13.69 ± 1.11, 1.19 ± 1.09, 1.69 ± 1.17 µg/mL in rat liver microsomes, respectively. Moreover, imperatorin and isoimperatorin were CYP450s inhibitors with IC < 10 µM for CYP1A2, 2C9, 2D6, and 3A4. Therefore, this study concluded that Radix could increase ligustrazine plasma concentration and then reinforce its pharmacological effect by inhibiting its metabolism through interference with CYP450s. This could be one mechanism for the synergy between Radix and ligustrazine on migraine treatment.
丹参含有香豆素，可能会影响细胞色素 P450 酶（CYP450）的活性，已与川芎嗪联合用于偏头痛的临床治疗，川芎嗪是 CYP450 的底物。然而，丹参和川芎嗪之间是否存在基于药代动力学的协同作用尚不清楚。在这项研究中，丹参的总香豆素提取物（TCE，50mg/kg，口服）通过减少抓头、降低血浆降钙素基因相关肽和血清一氧化氮水平，以及增加血浆内皮素水平，增强了川芎嗪的抗偏头痛活性大鼠（<0.05）。此外，药代动力学研究反映 TCE 增强了川芎嗪的浓度-时间曲线下面积，并延长了其在大鼠体内的平均滞留时间（<0.05）。此外，TCE、欧前胡素和异欧前胡素抑制川芎嗪代谢的 IC 分别为 5.0±1.02μg/mL、1.35±0.46μg/mL、4.81±1.14μg/mL在人肝微粒体中，以及 13.69±1.11μg/mL、1.19±1.09μg/mL、1.69±1.17μg/mL在大鼠肝微粒体中。此外，欧前胡素和异欧前胡素是 CYP450 抑制剂，对 CYP1A2、2C9、2D6 和 3A4 的 IC <10µM。因此，本研究得出结论，丹参可通过抑制 CYP450 来抑制其代谢，增加川芎嗪的血浆浓度，从而增强其药理作用。这可能是丹参和川芎嗪在偏头痛治疗中协同作用的机制之一。
