In Vitro Metabolism of Two Novel Tacrine Derivates ST09 and ST10 / 中国药学杂志

ABSTRACT

OBJECTIVE: To determin the in vitro metabolic stability of ST09 and ST10 in human liver microsomes (HLMs), and to evaluate their potential inhibitions on five HLM cytochrome P450 isoforms. METHODS: A liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to assess remaining concentration of ST09 and ST10 at designed time points during the HLM incubation. Six major metabolites of cytochrome P450 were simultaneously measured with LC-MS/MS, and the inhibitory effects of ST09 and ST10 were respectively evaluated with IC50 values. RESULTS: ST09 was extremely unstable in vitro, and t1/2 was less than 1 min. However, ST10, the major metabolite of ST09, was NADPH-independent metabolized in HLMs, while its t1/2 and microsomal intrinsic clearance (CLint) were 32 min and 0.043 mL·min-1·mg(protein)-1, respectively. IC50 values of ST09 and ST10 on CYP3A4 (midazolam as substrate), CYP3A4 (testosterone as substrate), CYP1A2, CYP2C9, CYP2C19 and CYP2D6 were 0.42/0.25, 1.27/0.81, 24.92/18.21, 36.53/54.34, 67.64/144.90, 6.43/5.30 μmol·L-1, respectively. CONCLUSION: ST09 and ST10 are extensively metabolized in vitro and both compounds had significant inhibition on CYP3A4 and CYP2D6.