Pharmacokinetic study on the interaction between pachymic acid and bavachin and its potential mechanism

Abstract

Context Pachymic acid and bavachin are commonly used drugs in the therapy of lung cancer. Objective The co-administration of pachymic acid and bavachin was investigated to evaluate their potential drug-drug interaction. Materials and methods The pharmacokinetics of bavachin (10 mg/kg) was studied in male Sprague-Dawley (SD) rats in the presence of pachymic acid (5 mg/kg) ( n = 6). The rats without pre-treatment of pachymic acid were set as the control and the pre-treatment of pachymic acid was conducted for 7 days before the administration of bavachin. The effect of pachymic acid on the activity of CYP2C9 was also estimated in rat liver microsomes with corresponding probe substrates. Results Pachymic acid influenced the pharmacokinetic profile of bavachin with the increased AUC (32.82 ± 4.61 vs. 19.43 ± 3.26 μg/L/h), the prolonged t 1/2 (3.21 ± 0.65 vs. 2.32 ± 0.28 h), and the decreased CLz / F (307.25 ± 44.35 vs. 523.81 ± 88.67 L/h/kg) in vivo . The metabolic stability of bavachin was enhanced by pachymic acid and the transport of bavachin was inhibited by pachymic acid. Pachymic acid was found to inhibit the activity of CYP2C9 with the IC 50 of 21.25 µM as well as the activity of P-gp . Discussion and conclusion The interaction between pachymic acid and bavachin results from the inhibition of CYP2C9 and P-gp . The dose of bavachin should be adjusted when combining with pachymic acid. The study design can be generalized to a broader study population with adjustment in the dose.

Pharmacological profiles and therapeutic applications of pachymic acid (Review)

“…In addition, treatment of human liver microsomes with PA (100 µ M) demonstrated that PA inhibits cytochrome P450 (CYP)3A4, 2E1 and 2C9, with IC 50 values of 15.04, 27.95 and 24.22 µ M, respectively, indicating potential drug-drug interactions ( 92 ). Moreover, after oral administration of PA (5 mg/kg) in rats, Zhang et al ( 93 ) indicated that PA increases the AUC and t 1 / 2 , decreases CL, enhances metabolic stability and further inhibits transport of natural flavonoid bavachin via regulation of CYP2C9 and P-glycoprotein.…”

Pachymic Acid Inhibits Growth and Metastatic Potential in Liver Cancer HepG2 and Huh7 Cells

“…It has been demonstrated that PA possesses diuretic, dormitive, anti-oxidant, anti-aging, anti-inflammatory and anticancer properties 10,11) . Additionally, the cell growth inhibition and cell apoptosis induction in breast cancer, lung cancer, ovarian cancer, pancreatic cancer, and gastric cancer cells have been extensively reported [12][13][14][15] . PA was able to regulated PTEN/AKT signaling pathway and the activity of Caspase 3/7 on osteosarcoma cells 16) , decreased the protein level of MMP-7 in pancreatic cancer 17) .…”