Assessment of the CYP1A2 Inhibition-Mediated Drug Interaction Potential for Pinocembrin Using <i>In Silico</i>, <i>In Vitro</i>, and <i>In Vivo</i> Approaches

Abstract

Pinocembrin, a bioflavonoid, is extensively used in complementary/alternative medicine. It turns out as a promising candidate against neurodegenerative diseases because of its multifaceted pharmacological action toward neuroprotection. However, literature evidence is still lacking for its inhibitory action on CYP1A2, which is responsible for xenobiotic metabolism leading to the generation of toxic metabolites and bioactivation of procarcinogens. In the present study, our aim was to evaluate the CYP1A2 inhibitory potential of pinocembrin via <i>in silico</i>, <i>in vitro</i>, and <i>in vivo</i> investigations. From the results of <i>in vitro</i> studies, pinocembrin is found to be a potent and competitive inhibitor of CYP1A2. <i>In vitro</i>-<i>in vivo</i> extrapolation results indicate the potential of pinocembrin to interact with CYP1A2 substrate drugs clinically. Molecular docking-based <i>in silico</i> studies demonstrate the strong interaction of pinocembrin with human CYP1A2. In <i>in vivo</i> investigations using a rat model, pinocembrin displayed a marked alteration in the plasma exposure of CYP1A2 substrate drugs, namely, caffeine and tacrine. In conclusion, pinocembrin has a potent CYP1A2 inhibitory action to cause drug interactions, and further confirmatory study is warranted at the clinical level.