The effects of CYP2B6 inactivators on the metabolism of ciprofol

• Published in: PloS one Vol. 19; no. 7; p. e0307995
• Main Authors: Lu, Ming, Zhang, Xiaorui, Li, Wenli, Li, Xiangchen, Li, Shan, Yin, Xiaoyu, Zhang, Zhiqing
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 29.07.2024; Public Library of Science (PLoS)
• Subjects: Analysis; Animals; Biology and Life Sciences; Carboxymethyl cellulose; Cellulose; Chromatography; Chromatography, High Pressure Liquid; Clinical trials; Clopidogrel; Clopidogrel - metabolism; Clopidogrel - pharmacology; Coumarins; Cytochrome P-450 CYP2B6 - metabolism; Cytochrome P-450 CYP2B6 Inhibitors - metabolism; Cytochrome P-450 CYP2B6 Inhibitors - pharmacology; Cytochrome P450; Cytochromes P450; Drug interaction; Drug Interactions; Ficusin - pharmacology; General anesthesia; Glucuronosyltransferase; High performance liquid chromatography; Humans; Inactivators; Liquid chromatography; Liver; Male; Mass spectrometry; Mass spectroscopy; Medicine and Health Sciences; Metabolism; Methylcellulose; Microsomes; Microsomes, Liver - metabolism; Phenylacetates; Physical Sciences; Plasma; Psoralen; Rats; Rats, Sprague-Dawley; Righting reflex; Scientific imaging; Tandem Mass Spectrometry; Thiophenes; Ticlopidine - analogs & derivatives; Ticlopidine - metabolism; Ticlopidine - pharmacology; Uridine; China; Beijing China; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0307995

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.