Metabolic profiling of lumateperone in vitro and in vivo by UPLC-Q Exactive Orbitrap HRMS, and its pharmacokinetic study in rat plasma by LC-MS/MS

• Published in: Journal of pharmaceutical and biomedical analysis Vol. 246; p. 116221
• Main Authors: Qiu, Yifan, Guo, Jing, Chen, Jindong, Zhang, Wenjing, Wang, Wenyan
• Format: Journal Article
• Language: English
• Published: England Elsevier B.V 15.08.2024
• Subjects: Administration, Oral; Animals; Antipsychotic Agents - administration & dosage; Antipsychotic Agents - blood; Antipsychotic Agents - pharmacokinetics; Biological Availability; Biotransformation; Chromatography, High Pressure Liquid - methods; Chromatography, Liquid - methods; Dogs; Humans; LC-MS/MS; Liquid Chromatography-Mass Spectrometry; Lumateperone; Male; Metabolite identification; Microsomes, Liver - metabolism; Pharmacokinetics; Piperazines - blood; Piperazines - pharmacokinetics; Rat plasma; Rats; Rats, Sprague-Dawley; Tandem Mass Spectrometry - methods; UPLC-Q exactive orbitrap HRMS; Lumateperone; LC-MS/MS; Metabolite identification; Pharmacokinetics; UPLC-Q exactive orbitrap HRMS; Rat plasma
• ISSN: 0731-7085; 1873-264X
• DOI: 10.1016/j.jpba.2024.116221

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. [Display omitted] •Metabolic profiling of lumateperone in vitro and in vivo and was firstly reported.•Fourteen phase I metabolites were found in vitro, indicating species difference.•Lumateperone was rapid absorbed and eliminated in rats, and metabolized extensively.•N-demethylated metabolite had the exposure levels comparable to lumateperone in rats.