Abstract：
Lumateperone is a novel agent approved by FDA for treatment of schizophrenia in adults. To elucidate the species differences in the of biotransformation of lumateperone and its pharmacokinetic (PK) characteristics in rats, the metabolite identification of lumateperone was carried out in rat, dog and human liver microsomes, and rat plasma after oral administration using UPLC-Q Exactive Orbitrap high-resolution mass spectrometry HRMS. Furtherly, the PK characteristics of lumateperone and its N-demethylated metabolite (M3) in rat plasma were investigated using a validated LC-MS/MS method following intravenous and oral administration. Fourteen phase I metabolites were found in liver microsomes and ten of them were observed in rat plasma. N-demethylation, carbonylation, dehydrogenation, and piperazine ring cleavage were main metabolic pathway of lumateperone. No unique metabolites were formed in human liver microsomes. After rapid absorption in rats, lumateperone was quickly metabolized and eliminated with bioavailability of less than 5%. The exposure level of M3 was about 1.5-fold higher than that of lumateperone in rat plasma. Lumatperone underwent extensive metabolism and was absorbed rapidly in rats. Metabolite M3 had equivalent or slightly higher exposure levels than lumateperone. This study provides essential PK information to facilitate further pharmacodynamic researches of lumateperone.
摘要：
Lumateperone是FDA批准的用于治疗成人精神分裂症的新型药物。为了阐明lumateperone生物转化的物种差异及其在大鼠体内的药代动力学（PK）特征，lumateperone的代谢物鉴定在大鼠中进行，狗和人类肝微粒体，口服后的大鼠血浆使用UPLC-QExactiveOrbitrap高分辨率质谱HRMS。更进一步,在静脉和口服给药后，使用经过验证的LC-MS/MS方法研究了大鼠血浆中lumateperone及其N-去甲基化代谢物（M3）的PK特征。在肝微粒体中发现了14种I相代谢物，在大鼠血浆中观察到了10种。N-去甲基化,羰基化,脱氢,哌嗪环裂解是洛美哌酮的主要代谢途径。在人肝微粒体中未形成独特的代谢物。在大鼠中快速吸收后，lumateperone被迅速代谢并消除,生物利用度低于5%.在大鼠血浆中，M3的暴露水平比lumateperone高约1.5倍。Lumatperone经历了广泛的代谢，并在大鼠中迅速吸收。代谢物M3的暴露水平与lumateperone相当或稍高。本研究提供了必要的PK信息，以促进lumateperone的进一步药效学研究。
