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Drug metabolites in the systemic circulation can be closely related to the safety or efficacy of drugs, so it is necessary to evaluate the pharmacokinetics of both the parent drug and its major metabolites in plasma. Bisthianostat, a novel histone deacetylase (HDAC) inhibitor, is currently under development. An LC-MS/MS method was developed and validated for the simultaneous determination of bisthianostat and its hydrolyzed N-hydroxyamide metabolite M351 in human plasma to evaluate their pharmacokinetic characteristics in humans. After extraction from the plasma by acetonitrile-induced protein precipitation, the analytes and endogenous substances were separated on a Waters BEH C18 column (2.1 mm×50 mm, 1.7 μm). The mobile phase consisted of acetonitrile and 5 mmol·L-1 ammonium acetate (containing 0.2% formic acid, v/v) for gradient elution. Positive electrospray ionization was performed using multiple reaction monitoring (MRM) with transitions of m/z 367.1→235.0 for bisthianostat, m/z 352.1→207.0 for M351, m/z 371.1→235.0 for d4-bisthianostat, and m/z 357.1→208.0 for d5-M351. The method was linear over a concentration range of 2.00-2000 ng·mL-1 for bisthianostat and 4.00-4 000 ng·mL-1 for M351. The results of quality control samples showed that the intra-and inter-day precision were no more than 6.2% for bisthianostat and 6.8% for M351. The accuracy ranged from -1.1% to 4.3% for bisthianostat and -0.5% to 4.9% for M351. The pharmacokinetic results show that after a single oral administration of 100 mg bisthianostat, the time to peak (tmax) of M351 in the plasma of three patients with tumors was significantly longer than that of the parent drug (tmax was 4.00 h and 0.67 h, respectively), and the Cmax and plasma exposure of M351 were about 1.7 times and 11 times higher, respectively, than that of the parent drug. This clinical trial was approved by the society of ethics and conducted in Renji Hospital, Shanghai Jiaotong University School of Medicine.
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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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