Context: Rotundic acid (RA), a plant-derived pentacyclic triterpene acid, has been reported to possess extensive pharmacological activities. The poor bioavailability limits its further development and potential clinic application.
Objective: To clarify the potential mechanism for poor oral bioavailability.
Materials and methods: The single-dose pharmacokinetics of orally administered RA (10 mg/kg) in Sprague-Dawley rats without or with verapamil (25 or 50 mg/kg) were investigated. Additionally, MDCKII-MDR1 and Caco-2 cell monolayers, five recombinant human cytochrome P450 (rhCYP) enzymes (1A2, 2C8, 2C9, 2D6 and 3A4), and rat liver microsomes were also conducted to investigate its potential mechanism.
Results: Verapamil could significantly affect the plasma concentration of RA. Co-administered verapamil at 25 and 50 mg/kg, the AUC0-∞ increased from 432 ± 64.2 to 539 ± 53.6 and 836 ± 116 ng × h/mL, respectively, and the oral clearance decreased from 23.6 ± 3.50 to 18.7 ± 1.85 and 12.2 ± 1.85 L/h/kg, respectively. The MDCKII-MDR1 cell assay showed that RA might be a P-gp substrate. The rhCYPs experiments indicated that RA was mainly metabolized by CYP3A4. Additionally, verapamil could increase the absorption of RA by inhibiting the activity of P-gp, and slow down the intrinsic clearance of RA from 48.5 ± 3.18 to 12.0 ± 1.06 µL/min/mg protein.
Discussion and conclusions: These findings indicated that verapamil could significantly affect the pharmacokinetic profiles of RA in rats. It was demonstrated that P-gp and CYP3A were involved in the transport and metabolism of RA, which might contribute to the low oral bioavailability of RA.
Keywords: CYP3A; Drug–drug interaction; P-gp; oral bioavailability.