Department of Pharmacy, The Second Hospital of Hebei Medical University, Shijiazhuang, China.
Department of Pharmacy, Hebei General Hospital, Shijiazhuang, China.
PLoS One. 2024 Jul 29;19(7):e0307995. doi: 10.1371/journal.pone.0307995. eCollection 2024.
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.
西普罗夫是中国研发的一种新型短效静脉麻醉剂，主要通过细胞色素 P450 2B6（CYP2B6）和尿苷二磷酸葡萄糖醛酸基转移酶 1A9（UGT1A9）代谢。目前，尚无充分证据支持西普罗夫与 CYP2B6 抑制剂之间发生药物相互作用。本研究建立了高效液相色谱-串联质谱（HPLC-MS/MS）法来评估西普罗夫的浓度，并研究了补骨脂素和氯吡格雷对肝微粒体和大鼠中西普罗夫代谢的影响。在大鼠和人肝微粒体中，补骨脂素的半数抑制浓度（IC50）值分别为 63.31 μmol·L-1和 34.05 μmol·L-1，对西普罗夫代谢表现出轻度抑制作用，而氯吡格雷的 IC50 值分别为 6.380 μmol·L-1和 2.565 μmol·L-1，表现出中度抑制作用。SD 大鼠随机分为 3 组：补骨脂素（27 mg·kg-1）、氯吡格雷（7.5 mg·kg-1）和等体积 0.5%羧甲基纤维素。7 天后，所有大鼠均注射 2.4 mg·kg-1西普罗夫。与对照组相比，补骨脂素组和氯吡格雷组的西普罗夫 AUC 和 MRT 值显著增加，而 CL 值显著降低。此外，补骨脂素组和氯吡格雷组的翻正反射消失潜伏期（LORR）分别延长了 16.1%和 23.0%。综上所述，补骨脂素和氯吡格雷均不同程度地抑制西普罗夫的代谢，并延长大鼠的 LORR 持续时间。
