氯丙嗪在不同种属肝微粒体中代谢差异研究

采用体外肝微粒体孵育实验研究氯丙嗪在鼠、猪、鸡肝微粒体的代谢速率及代谢产物。利用液相色谱-串联质谱测定不同时间点氯丙嗪的峰面积，计算氯丙嗪的体外代谢率、代谢半衰期（T1/2）及固有清除率（CLint），通过氯丙嗪及其代谢产物的保留时间、碎片离子等信息，推断氯丙嗪的代谢产物和代谢途径。结果表明，在猪、鼠、鸡肝微粒体孵育体系中，氯丙嗪的T1/2分别为18.2、173.3、346.5 min，CLint分别为76.2、8.0、4.0 μL/(min·mg)。在3种肝微粒体孵育体系中共发现8种代谢产物，在鼠、猪和鸡肝微粒体孵育体系中分别发现5种、7种和4种氯丙嗪代谢产物，均检测出产物氯丙嗪亚砜、去甲基氯丙嗪、6-羟基氯丙嗪和7-羟基氯丙嗪。氯丙嗪在肝微粒体孵育体系中的代谢途径以氧化、羟基化和去甲基反应为主，其在猪肝微粒体孵育体系中代谢和清除速度最快，其次是鼠、鸡，在不同种属肝微粒体孵育体系中代谢产物的种类和含量存在差异。

Metabolism of Chlorpromazine in Liver Microsomes of Different Species in Vitro

The metabolic rates and metabolites of chlorpromazine were studied by in vitro metabolism experiments with liver microsomes of rat, pig, and chicken. The residual chlorpromazine in the incubation systems of liver microsome with different reaction time (0, 20, 60, 120 min) were measured by high performance liquid chromatography-triple-quadrupole tandem mass spectrometry (HPLC-MS/MS) with full scan and selection ion monitoring (SIM) modes. The metabolic precents of chlorpromazine were used to calculate the half-life (T1/2) and intrinsic clearance rate (CLint) in the three incubation systems. Main metabolites were identified by the retention time and m/z of fragment ions of chlorpromazine and its metabolites, and possible metabolic pathways were inferred based on the information of metabolites. The results showed that the T1/2 values of chlorpromazine were 18.2, 173.3 and 346.5 min, and the Clint values were 76.2, 8.0 and 4.0 μL/(min·mg) in the liver microsomes of pig, rat and chicken, respectively. A total of eight metabolites were found in the liver microsome incubation systems. There were five metabolites found in the liver microsome incubation system of rat, including prochlorperazine sulfoxide, demethyl chlorpromazine, dimethyl chlorpromazine, 6-hydroxy chlorpromazine and 7-hydroxy chlorpromazine, and demethyl chlorpromazine had the highest abundance. Seven metabolites including prochlorperazine sulfoxide, demethyl chlorpromazine, 6-hydroxy chlorpromazine, 7-hydroxy chlorpromazine, 6-hydroxy demethyl chlorpromazine (or 7-hydroxy demethyl chlorpromazine) and two of 6-hydroxy chlorpromazine sulfoxide, 7-hydroxy chlorpromazine sulfoxide and 6, 7-dihydroxy chlorpromazine were found in the liver microsome incubation system of pig with the largest abundance for 6-hydroxy chlorpromazine sulfoxide (or 7-hydroxy chlorpromazine sulfoxide, 6,7-dihydroxy chlorpromazine). Four metabolites including prochlorperazine sulfoxide, dimethyl chlorpromazine, 6-hydroxy chlorpromazine and 7-hydroxy chlorpromazine were found in the liver microsome incubation system of chicken, and dimethyl chlorpromazine had the highest abundance. Four metabolites of chlorpromazine including prochlorperazine sulfoxide, dimethyl chlorpromazine, 6-hydroxy chlorpromazine and 7-hydroxy chlorpromazine were simultaneously detected in the three liver microsomal incubation systems. Although there were different metabolites in the incubation systems of different species, main metabolic processes of chlorpromazine were involved in oxidation, hydroxylation and demethylation reactions. In general, these results showed that chlorpromazine had the fastest metabolized and clearance rates in the pig liver microsome incubation system, followed by rat and chicken, and there were significant differences in the types and contents of the metabolites in the liver microsome incubation system of different species. This study is of significance for revealing the pharmacokinetics and potential toxicity of chlorpromazine in different species.