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To explore the effects of psoralen and clopidogrel on metabolism of ciprofol in human liver microsomes.
A high performance liquid chromatography-tandem mass spectrometry method for the detection of ciprofol concentrations in human liver microsomes was established, and the specificity, linearity and lower limit of quantitation, precision, recovery rate, matrix effect and stability of this method were investigated. A series of remaining concentrations of ciprofol after co-incubation of with human liver microsomes were detected, and the results were substituted into GraphPad Prism 8 software to calculate the kinetic parameters of the enzymatic reaction of ciprofol in human liver microsomes. Afterwards, psoralen and clopidogrel were co-incubated with ciprofol, respectively, and the median inhibitory concentrations (IC50) were calculated to investigate the effects of the two cytochrome P450 2B6 (CYP2B6) inactivators on ciprofol metabolism.
Ciprofol was linear in the range of 1.00-100.00 μg·mL-1. The standard curve equation was y=0.15x-0.11 (r=0.999 2); the lower limit of quantification was 1.00 μg·mL-1. The relative standard deviation (RSD) values for intra-day and inter-day precision were less than 7%, with relative error not exceeding ±5%. The extraction recoveries and matrix effects were 92.69%-99.62% and 94.77%-101.84%, respectively. In addition, the samples exhibited satisfactory stabilities incubated in a water bath at 37 ℃ for 2 h, stored at room temperature for 8 h or processed and placed in the autosampler for 24 h. The Michaelis constant (Km), maximum reaction rate (Vmax) and intrinsic clearance (CLint) of ciprofol were 37.81 μg·mL-1, 41.54 ng·min-1·mg protein-1 and 0.91 mL·min-1·mg-1, respectively. Psoralen and clopidogrel inhibited the metabolism of ciprofol in human liver microsomes in a dose-dependent manner with IC50 values of 30.25 and 2.09 μmol·L-1, showing mild and moderate inhibition of the metabolism of ciprofol, respectively.
Psoralen and clopidogrel can reduce the metabolism of ciprofol in human liver microsomes.
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| 科 Family | 属数 Number of genus | 种数 Number of species | 占总种数比例 Percentage of total species (%) | 属 Genus | 种数 Number of species | 占总种数比例 Percentage of total species (%) |
|---|---|---|---|---|---|---|
| 鹅膏菌科Amanitaceae | 2 | 11 | 5.26 | 鹅膏菌属 Amanita | 10 | 4.78 |
| 小菇科 Mycenaceae | 2 | 12 | 5.74 | 丝盖伞属 Inocybe | 5 | 2.39 |
| 多孔菌科 Polyporaceae | 8 | 14 | 6.70 | 蜡蘑属 Laccaria | 5 | 2.39 |
| 红菇科 Russulaceae | 3 | 23 | 11.00 | 小皮伞属 Marasmius | 6 | 2.87 |
| 小菇属 Mycena | 11 | 5.26 | ||||
| 光柄菇属 Pluteus | 5 | 2.39 | ||||
| 红菇属 Russula | 17 | 8.13 | ||||
| 栓菌属 Trametes | 5 | 2.39 |
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