Inhibitory effects characteristics of polysaccharide of Polygonati Rhizome on cytochrome P450 enzymes

Purpose As the major active ingredient of Polygonatum sibriricum Red., polysaccharide of Polygonati Rhizome (PSP) has been reported to possess various pharmacological activities, especially for the treatment of chronic disorders in the elderly. This study evaluated the effect of PSP on the activities of major cytochrome P450 enzymes (CYP450) isoforms, aiming to provide theoretical reference for its co-prescription with other drugs and prevent the risk of adverse drug-drug interaction. Methods The activities of CYP450 isoforms were assessed in human liver microsomes with specific probe substances. Through Lineweaver-Burk fitting models, the effect of PSP on the activity of inhibited CYP450 isoforms was characterized by competitive and non-competitive models. Dose-dependent and time-dependent experiments were also performed to completely understand the inhibition. Results Among experimental isoforms, PSP significantly inhibited the activities of CYP2C9, 2D6, and 3A4 in a concentration-dependent manner with IC50 values of 14.01, 17.63, and 5.33 mu M. The inhibition of CYP2C9 and 2D6 was best fitted with the competitive model with the K-i values of 7.15 and 8.92 mu M, respectively, while the inhibition of CYP3A4 was non-competitive with the K-i value of 2.63 mu M. Additionally, the inhibition of CYP3A4 by PSP also showed time-dependent characteristics with the inhibition parameters, K-I of 1.273 mu M-1 and K-inact of 0.036 min(-1). Conclusion PSP exerted moderate inhibition on CYP2C9 and 2D6 and strong inhibition of CYP3A4. The dosage of CYP2C9-, 2D6-, and 3A4-metabolized drugs should be adjusted when co-administrated with PSP and its sourced herbs.