School of Pharmaceutical Sciences, Peking University, Beijing 100191, PR China; Institute of Basic Medical Sciences of Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing key laboratory of pharmacology of Chinese material medica, Beijing 10091, PR China.
Institute of Basic Medical Sciences of Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing key laboratory of pharmacology of Chinese material medica, Beijing 10091, PR China.
Phytomedicine. 2018 Jan 1;38:125-134. doi: 10.1016/j.phymed.2017.02.007. Epub 2017 Feb 27.
Sailuotong (SLT) is a standard Chinese preparation made from extracts of Panax ginseng (ginseng), Ginkgo biloba (ginkgo), and Crocus sativus (saffron). Preliminary clinical trials and animal experiments have demonstrated that SLT could improve cognition of vascular dementia (VD).
To avoid incident drug-drug interaction which is easily encountered in patients of VD, the potential influence of SLT on main drug-metabolic cytochromes P450 enzymes (CYP450) was investigated.
A "cocktail probes" approach was employed to evaluate the activities of CYP450. A rapid and selective analysis method was developed to examine 5 CYP probe drugs and their specific metabolites in plasma by using online SPE followed by a single LC-MS/MS run. After pretreatment for 2 weeks with SLT, ginseng, gingko, saffron or water (control), a cocktail solution containing caffeine, losartan, omeprazole, dextromethorphan and midazolam was given to rats orally. The plasma was obtained at different time intervals and then measured for the concentration of probes and their metabolites using developed SPE-LC-MS/MS method. Activity of five isozymes was estimated by comparing plasma pharmacokinetics of substrates and their metabolites (caffeine/paraxanthine for CYP1A2, losartan/E-3174 for CYP2C11, omeprazole/5-hydroxyl omeprazole for CYP2C6, dextromethorphan/dextrophan for CYP2D2 and midazolam/1-hydroxyl midazolam for CYP3A1/2) between control and drug treatment groups.
Compared with control group, repeated administration of SLT induced CYP1A2 by enhancing AUC / AUC to144%. The influence is attributed to its herbal component of ginseng to a large extent. Meanwhile, metabolic ability towards losartan was significantly elevated in SLT and gingko group by 31% and 25% respectively, indicating weak induction of CYP2C11 in rats. The analysis on probes of omeprazole and dextromethorphan showed a lack of influence on CYP 2C6 and CYP2D2 in all treated groups. In terms of CYP3A1/2, SLT decreased AUC ratio of 1-hydroxyl midazolam to midazolam by 39% and extended the half-life of midazolam apparently. Besides, significantly decreased systematic exposure of midazolam suggested the inhibition on metabolism of CYP3A1/2 is likely secondary to the interaction on absorption at intestinal level. The inhibition of SLT on CYP3A was likely attributed to ginseng and gingko cooperatively.
Further observation on herb-drug interaction should be considered during clinical application of SLT.
sailuotong（SLT）是一种标准的中药制剂，由人参、银杏叶和西红花提取物制成。初步的临床研究和动物实验表明，SLT 可改善血管性痴呆（VD）患者的认知能力。
为避免血管性痴呆患者易发生的药物-药物相互作用，本研究考察了 SLT 对主要药物代谢细胞色素 P450 酶（CYP450）的潜在影响。
采用“鸡尾酒探针”法评价 CYP450 活性。建立了一种快速、选择性的分析方法，采用在线 SPE 结合单 LC-MS/MS 分析，检测血浆中 5 种 CYP 探针药物及其特异性代谢物。大鼠给予 SLT、人参、银杏叶、西红花或水（对照）预处理 2 周后，给予包含咖啡因、洛沙坦、奥美拉唑、右美沙芬和咪达唑仑的鸡尾酒溶液口服。在不同时间间隔采集血浆，采用所建立的 SPE-LC-MS/MS 方法测定探针及其代谢物的浓度。通过比较对照和药物处理组中底物及其代谢物（咖啡因/茶碱用于 CYP1A2，洛沙坦/E-3174 用于 CYP2C11，奥美拉唑/5-羟奥美拉唑用于 CYP2C6，右美沙芬/右啡烷用于 CYP2D2，咪达唑仑/1-羟咪达唑仑用于 CYP3A1/2）的药代动力学参数，评估五种同工酶的活性。
与对照组相比，重复给予 SLT 通过增加 AUC / AUC 至 144%，诱导 CYP1A2。这种影响在很大程度上归因于其草药成分人参。同时，SLT 和银杏组中洛沙坦的代谢能力分别显著提高了 31%和 25%，表明 CYP2C11 在大鼠中被弱诱导。对奥美拉唑和右美沙芬探针的分析表明，所有治疗组对 CYP2C6 和 CYP2D2 无影响。对于 CYP3A1/2，SLT 使 1-羟咪达唑仑与咪达唑仑的 AUC 比值降低了 39%，并明显延长了咪达唑仑的半衰期。此外，咪达唑仑的系统暴露量明显减少表明，CYP3A1/2 的代谢抑制可能是肠道水平吸收相互作用的结果。SLT 对 CYP3A 的抑制可能归因于人参和银杏叶的协同作用。
在 SLT 的临床应用中，应考虑进一步观察草药-药物相互作用。
