Pharmacokinetic interaction between rhynchopylline and pellodendrine via CYP450 enzymes and P-gp

CONTEXT: Rhynchopylline and pellodendrine are major extractions of commonly used Chinese medicine in gynaecology. The interaction between these two compounds could affect treatment efficiency and even result in toxicity during their co-administration in gynaecological prescription. OBJECTIVE: The pharmacokinetic interaction between rhynchopylline and pellodendrine and the potential mechanism were investigated in this study. MATERIALS AND METHODS: Sprague-Dawley rats were randomly divided into four groups to investigate the pharmacokinetic interaction between rhynchopylline (30 mg/kg) and pellodendrine (20 mg/kg) with single dose of these two drugs as the control. The transport of rhynchopylline was evaluated in the Caco-2 cell model. Additionally, the metabolic stability and the activity of corresponding CYP450 enzymes were assessed in rat liver microsomes. RESULTS: The pharmacokinetic profile of rhynchopylline was dramatically affected by pellodendrine with the increased area under the pharmacokinetic curve (3080.14 ± 454.54 vs. 1728.08 ± 220.598 μg/L*h), C(max) (395.1 ± 18.58 vs. 249.1 ± 16.20 μg/L), prolonged t(1/2) (9.74 ± 2.94 vs. 4.81 ± 0.42 h) and the reduced clearance rate (from 11.39 ± 1.37 to 5.67 ± 1.42 L/h/kg). No significant changes were observed in the pharmacokinetics of pellodendrine. The transport of rhynchopylline was significantly inhibited by pellodendrine with a decreasing efflux ratio (1.43 vs. 1.79). Pellodendrine significantly inhibited the activity of CYP1A2 and CYP2C9 with IC(50) values of 22.99 and 16.23 μM, which are critical enzymes responsible for the metabolism of rhynchopylline. DISCUSSION AND CONCLUSIONS: The adverse interaction between rhynchopylline and pellodendrine draws attention to the co-administration of these two herbs and provides a reference for further investigations with a broader study population.