Wang Xin, Lee Wayne Y W, Or Penelope M Y, Yeung John H K
Department of Pharmacology, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, NT, Hong Kong SAR, China.
Phytomedicine. 2009 Aug;16(8):712-25. doi: 10.1016/j.phymed.2009.03.004. Epub 2009 Apr 28.
This study explored the effects of Danshen on metabolism/pharmacokinetics of model CYP1A2 substrates and hepatic CYP1A2 expression in rats. The effects of Danshen and tanshinones on CYP1A2 activity was determined by metabolism of model substrates in vitro (phenacetin) and in vivo (caffeine). HPLC was used to determine model substrates/metabolites. The effect of Danshen on CYP1A2 expression was determined by Western blot. Tanshinones (1.25-50 microM) competitively inhibited phenacetin O-deethylation in vitro. Inhibition kinetics studies showed the K(i) values were in the order: dihydrotanshinone (3.64 microM), cryptotanshinone (4.07 microM), tanshinone I (22.6 microM) and tanshinone IIA (23.8 microM), furafylline (35.8 microM), a CYP1A2 inhibitor. The Ki of Danshen extract (mainly tanshinones) was 72 microg/ml. Acute Danshen extract treatment (50-200mg/kg, i.p.) decreased metabolism of caffeine to paraxanthine, with overall decrease in caffeine clearance (14-22%); increase in AUC (11-25%) and plasma T(1/2) (12-16%). Danshen treatment with (100mg/kg/day, i.p. or 200mg/kg/day, p.o.) for three or fourteen days showed similar pharmacokinetic changes of the CYP1A2 probe substrate without affecting CYP1A2 expression. This study demonstrated that major tanshinones competitively inhibited the metabolism of model CYP1A2 probe substrates but had no effect on rat CYP1A2 expression.
本研究探讨了丹参对大鼠体内模型CYP1A2底物代谢/药代动力学及肝脏CYP1A2表达的影响。通过体外（非那西丁）和体内（咖啡因）模型底物的代谢来确定丹参和丹参酮对CYP1A2活性的影响。采用高效液相色谱法测定模型底物/代谢产物。通过蛋白质印迹法确定丹参对CYP1A2表达的影响。丹参酮（1.25 - 50微摩尔）在体外竞争性抑制非那西丁O - 去乙基化。抑制动力学研究表明，抑制常数（K(i)）值的顺序为：二氢丹参酮（3.64微摩尔）、隐丹参酮（4.07微摩尔）、丹参酮I（22.6微摩尔）和丹参酮IIA（23.8微摩尔），CYP1A2抑制剂呋拉茶碱（35.8微摩尔）。丹参提取物（主要为丹参酮）的Ki为72微克/毫升。急性给予丹参提取物（50 - 200毫克/千克，腹腔注射）可降低咖啡因代谢为副黄嘌呤的水平，咖啡因清除率总体降低（14 - 22%）；曲线下面积（AUC）增加（11 - 25%），血浆半衰期（T(1/2)）增加（12 - 16%）。连续三天或十四天给予丹参（100毫克/千克/天，腹腔注射或200毫克/千克/天，口服）显示CYP1A2探针底物有相似的药代动力学变化，但不影响CYP1A2表达。本研究表明，主要的丹参酮竞争性抑制模型CYP1A2探针底物的代谢，但对大鼠CYP1A2表达无影响。
