目的 考察中药复方艾可清对药物代谢酶和抗艾滋病病毒（HIV）药物克力芝组分洛匹那韦（LPV）和利托 那韦（RTV）药物代谢动力学的影响。方法 将人肝微粒体与混合探针和艾可清共孵育，用高效液相色谱-质谱 （HPLC-MS）联用技术测定探针的含量变化，计算艾可清对肝微粒体中药物代谢酶细胞色素 P450 不同亚型的半 数抑制浓度（IC50），确定艾可清抑制的 P450 亚型。建立 HPLC-MS 法同时测定大鼠血浆中 LPV 和 RTV 含量； 大鼠灌胃艾可清或溶媒，每日 1 次，连续 7 d，末次灌胃艾可清后 0.5 h 灌胃克力芝，检测 LPV 和 RTV 的血药 浓度，分析艾可清对其药代动力学参数的影响。结果 艾可清甲醇提取物在 0~500 µg·mL-1 浓度范围内，对 P450 代谢酶表型 CYP2D6、CYP2C8、CYP2E1、CYP2C19、CYP1A2、CYP2B6、CYP2C9 和 CYP3A4 酶活性的 IC50 值依次为 7.7、75.3、144.0、99.5、43.5、104.5、49.3 和 204.9 µg·mL-1。建立了定量分析 LPV 和 RTV 的 HPLC-MS/MS 方法，LPV 和 RTV 分别在 30~10 000 ng·mL-1 和 3~1 000 ng·mL-1 范围呈线性关系，最低定量限 分别为 30 ng·mL-1 和 3 ng·mL-1，日内、日间精密度均小于 5%，LPV 和 RTV 的准确度均在 96.3%~109.0% 之 间，提取回收率均不小于 88.7%，基质效应均在 93.8%~105.0% 之间，血浆样品稳定性较好。与克力芝组比较， 艾可清与克力芝联用组 LPV 的非房室模型参数 AUC0-t、AUC0-∞、MRT0-t、t1/2z、tmax、Vz/F、Clz/F、Cmax均无明显影 响（P＞0.05），但可延长 MRT0-∞（P＜0.05）；联用组 RTV 所有药动学参数均无明显影响（P＞0.05）。结论 艾可 清对人肝脏药物代谢酶 CYP450 中 8 个亚型有不同程度的抑制作用，其中对 CYP2D6 的抑制作用最明显；大鼠 灌胃人等效剂量艾可清对洛匹那韦和利托那韦的药代动力学参数无明显的影响。

Objective To investigate the effects of Aikeqing （AKQ），a compound of Chinese medicine，on drugmetabolizing activity and on the pharmacokinetic parameters of HIV-1 protease inhibitors lopinavir （LPV） and ritonavir （RTV） in Kaletra tablets. Methods Human liver microsomes were co-incubated with mixed probes and AKQ. HPLC-MS was employed to measure the content of probe. Half-inhibitory concentration （IC50） of AKQ on different subtypes of cytochrome P450 enzymes involved in drug metabolism of liver microsomes was calculated. The P450 subtype，whose activity was significantly inhibited by AKQ was then identified. HPLC-MS analytical method for simultaneous determination of LPV and RTV in rat plasma was established. SD rats were orally given AKQ or vehicle once a day for 7 consecutive days. After half an hour of the last gavage of AKQ，the rats were given Kaletra by intragastric administration. Then，the blood concentration of LPV and RTV were measured and the effect of AKQ on pharmacokinetic parameters of LPV and RTV were analyzed. Results The methanol extract of AKQ at the concentrations of 0~500 µg·mL-1 showed inhibitory effects on the metabolic activity of CYP2D6， CYP2C8、 CYP2E1，CYP2C19，CYP1A2，CYP2B6，CYP2C9 and CYP3A4，with IC50 values of 7.7，75.3，144.0，99.5， 43.5， 104.5， 49.3 and 204.9 µg·mL-1， respectively. An HPLC-MS/MS method was established for simultaneous quantification of LPV and RTV in blood samples. LPV and RTV showed linear relationships in the ranges of 30～ 10 000 ng·mL-1 and 3~1 000 ng·mL-1，respectively. The lowest limits of quantification were 30 ng·mL-1 and 3 ng·mL-1. Intra-day and inter-day precision were all less than 5%，and the accuracy of LPV and RTV was in the range of 96.3%~109%. The extraction recovery rates were not less than 88.7%，the matrix effects were 93.8%~105.0%，and the plasma samples were stable. Compared with Kaletra group， there was no significant changes in noncompartmental model parameters including AUC0-t，AUC0-∞，MRT0-t，t1/2z，tmax，Vz/F，Clz/F and Cmax of LPV in AKQ + Kaletra group （P＞0.05）. But MRT0-∞ was found to be obviously affected by AKQ （P＜0.05）. All pharmacokinetic parameters of RTV showed no significant change in AKQ+ Kaletra group （P＞0.05）. Conclusion Aikeqing exhibited varying degrees of inhibitory effects on 8 human drug-metabolizing cytochromes P450， especially CYP2D6. A human-equivalent dose of Aikeqing does not affect the pharmacokinetic parameters of lopinavir and ritonavir in rats.

R285.5

国家科技重大专项课题（2014ZX10005002）。