Effect of plantamajoside on the pharmacokinetics of nifedipine in rats and the underlying mechanisms

Plantamajoside was reported to possess blood pressure-lowering effects. This study explores how plantamajoside affects the pharmacokinetics of nifedipine, providing valuable insights for clinical drug use.This study examined the effect of plantamajoside on nifedipine pharmacokinetics. Sprague-Dawley rats (n = 6 per group) were administered nifedipine orally, either alone or after pre-treatment with plantamajoside. Blood concentrations of nifedipine were measured using liquid chromatography-tandem mass spectrometry. The effects of plantamajoside on nifedipine metabolic stability and cytochrome P450 3A (CYP3A) activity were evaluated in rat liver microsomes (RLMs).Co-administration of nifedipine with plantamajoside altered its pharmacokinetics, including elevated peak plasma concentration (Cmax), increased area under the concentration-time curve (AUC)(0–t), prolonged elimination half-life (t1/2), and reduced apparent clearance (CL/F). In vitro, plantamajoside enhanced the metabolic stability of nifedipine, extending its t1/2 and lowering intrinsic clearance. Plantamajoside also inhibited CYP3A activity in RLMs (half maximal inhibitory concentration, IC50 = 13.96 μM; inhibition constant, Ki = 7.10 μM).The increased nifedipine exposure in rats could be attributed to the inhibition of CYP3A-mediated metabolism by plantamajoside. Given the role of orthologous CYP3A4 in humans, this interaction may enhance antihypertensive efficacy but could also increase the risk of severe hypotension clinically.