Open AccessIn vitro metabolic characterization of orbitazine, a novel derivative of the PAC‐1 anticancer agent
Author(s) -
Li Fang,
Han Xuhua,
Chen Yanfen,
Wang Shanshan,
Cheng Zeneng,
Hu Gaoyun,
Liu Wenjie,
Zhu Qubo
Publication year - 2020
Publication title -
journal of pharmacy and pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.745
H-Index - 118
eISSN - 2042-7158
pISSN - 0022-3573
DOI - 10.1111/jphp.13296
Subject(s) - cyp1a2 , cyp3a4 , cyp2b6 , microsome , chemistry , cyp2d6 , in vitro , enzyme , metabolic pathway , biochemistry , pharmacology , cyp2c9 , cytochrome p450 , metabolism , biology
Objectives The in vitro evaluation of new drugs is an important step in the drug development pipeline. Orbitazine is a derivative of PAC‐1 that has substituted the functional group homopiperazine ring with a piperazine ring. The purpose of this study was to assess the metabolic profile of orbitazine. Methods Metabolism was characterized in vitro by incubating liver microsomes with metabolize orbitazine or the classical metabolic enzyme substrates. High performance liquid chromatography (HPLC) and LC‐MS/MS were used to identify the parent drugs and metabolites of orbitazine or metabolic enzyme substrates. Key findings There was no difference in metabolic stability or metabolites across different species. The metabolites included a debenzyl compound and several hydroxyl compounds, defined as M1(316), M2(440), M3(422), M4(422) and M5(422). We found that orbitazine was metabolized by CYP3A4, CYP2C9 and CYP2D6 in a human liver microsomes incubation system. Orbitazine had no significant inhibitory effect on CYP1A2, CYP2B6, CYP2C9, or CYP2C19 in human liver microsomes, but showed a dose‐dependent inhibition of CYP2C8, CYP2D6 and CYP3A4; and there was no orbitazine‐mediated induction of CYP1A2, CYP2B6, CYP3A4 or mRNA expression in hepatocytes. Conclusions This in vitro data on the metabolism of orbitazine may provide valuable information to support further clinical progression as a potential therapeutic molecule.