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Abstract：
Ciprofol is a novel short-acting intravenous anaesthetic developed in China that is mainly metabolized by cytochrome P450 2B6 (CYP2B6) and uridine diphosphate glucuronosyltransferase 1A9 (UGT1A9). Currently, insufficient evidence is available to support drug‒drug interactions between ciprofol and CYP2B6 inactivators. Here, we established a high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method to assess the concentration of ciprofol and investigated the effects of psoralen and clopidogrel on the metabolism of ciprofol in liver microsomes and rats. In rat and human liver microsomes, the median inhibitory concentration (IC50) values of psoralen were 63.31 μmol·L-1 and 34.05 μmol·L-1, respectively, showing mild inhibitory effects on ciprofol metabolism, whereas the IC50 values of clopidogrel were 6.380 μmol·L-1 and 2.565 μmol·L-1, respectively, with moderate inhibitory effects. SD rats were randomly divided into three groups: psoralen (27 mg·kg-1), clopidogrel (7.5 mg·kg-1), and the same volume of 0.5% carboxy methyl cellulose. After 7 days, all rats were injected with 2.4 mg·kg-1 ciprofol. Compared with the control group, the AUC and MRT values of ciprofol in the psoralen and clopidogrel groups were significantly greater, whereas the CL values were significantly lower. In addition, the durations of loss of righting reflex (LORR) in the psoralen and clopidogrel groups were 16.1% and 23.0% longer than that in the control group, respectively. In conclusion, psoralen and clopidogrel inhibit ciprofol metabolism to different degrees and prolong the duration of LORR in rats.
摘要：
环丙泊酚是我国开发的一种新型短效静脉麻醉药，主要由细胞色素P4502B6（CYP2B6）和尿苷二磷酸葡萄糖醛酸基转移酶1A9（UGT1A9）代谢。目前,没有足够的证据支持环丙泊酚和CYP2B6灭活剂之间的药物-药物相互作用.这里,建立了高效液相色谱-串联质谱(HPLC-MS/MS)检测方法,研究了补骨脂素和氯吡格雷对大鼠肝微粒体和大鼠体内顺丙酚代谢的影响。在大鼠和人类肝微粒体中，补骨脂素的中位抑制浓度(IC50)分别为63.31μmol·L-1和34.05μmol·L-1,对顺丙泊酚代谢表现出温和的抑制作用，氯吡格雷的IC50值分别为6.380μmol·L-1和2.565μmol·L-1,具有中等抑制作用。SD大鼠随机分为3组:补骨脂素(27mg·kg-1),氯吡格雷（7.5mg·kg-1），和相同体积的0.5%羧甲基纤维素。7天后,所有大鼠均注射2.4mg·kg-1的顺丙泊酚。与对照组相比,补骨脂素和氯吡格雷组顺丙泊酚的AUC和MRT值明显更大,而CL值显着降低。此外,补骨脂素和氯吡格雷组的康复反射（LORR）丧失持续时间分别比对照组长16.1%和23.0%，分别。总之,补骨脂素和氯吡格雷均能不同程度地抑制大鼠顺丙酚代谢，延长LORR持续时间。
