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In vitrometabolic mapping of neobavaisoflavone in human cytochromes P450 and UDP-glucuronosyltransferase enzymes by ultra high-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry

Jinjin Xu,Mengsen Li,Zhihong Yao,Yezi Zhang,Shishi Li,Liufang Hu,Zifei Qin,Frank J. Gonzalez,Xinsheng Yao

Neobavaisoflavone (NBIF), a phenolic compound isolated from Psoralea corylifolia L., possesses several significant biological properties. However, the pharmacokinetic behaviors of NBIF have been characterized as rapid oral absorption, high clearance, and poor oral bioavailability. We found that NBIF underwent massive glucuronidation and oxidation by human liver microsomes (HLM) in this study with the intrinsic clearance ( CL int ) values of 12.43, 10.04, 2.01, and 6.99 μL/min/mg for M2, M3, M4, and M5, respectively. Additionally, the CL int values of G1 and G2 by HLM were 271.90 and 651.38 μL/min/mg, respectively, whereas their respective parameters were 59.96 and 949.01 μL/min/mg by human intestine microsomes (HIM). Reaction phenotyping results indicated that CYP1A1, 1A2, 2C8, and 2C19 were the main contributors to M4 (34.96 μL/min/mg), M3 (29.45 μL/min/mg), M3 (13.16 μL/min/mg), and M2 (63.42 μL/min/mg), respectively. UGT1A1, 1A7, 1A8, and 1A9 mainly catalyzed the formation of G1 (250.87 μL/min/mg), G2 (438.15 μL/min/mg), G1 (92.68 μL/min/mg), and G2 (1073.25 μL/min/mg), respectively. Activity correlation analysis assays showed that phenacetin- N -deacetylation was strongly correlated to M3 ( r  = 0.860, p  = 0.003) and M4 ( r  = 0.775, p  = 0.014) in nine individual HLMs, while significant activity correlations were detected between paclitaxel-6-hydroxylation and M2 ( r  = 0.675, p  = 0.046) and M3 ( r  = 0.829, p  = 0.006). There was a strong correlation between β-estradiol-3- O -glucuronide and G1 ( r  = 0.822, p  = 0.007) and G2 ( r  = 0.689, p  = 0.040), as well as between propofol- O -glucuronidation and G1 ( r  = 0.768, p  = 0.016) and G2 ( r  = 0.860, p  = 0.003). Moreover, the phase I metabolism and glucuronidation of NBIF revealed marked species differences, and mice are the best animal model for investigating the metabolism of NBIF in humans. Taken together, characterization of NBIF-related metabolic pathways involving in CYP1A1, 1A2, 2C8, 2C19, and UGT1A1, 1A7, 1A8, 1A9 are helpful for understanding the pharmacokinetic behaviors and conducting in-depth pharmacological studies.