Influence of verapamil on the pharmacokinetics of rotundic acid in rats and its potential mechanism. (1st January 2021)

• Record Type: Journal Article
• Authors: Shang, Haihua; Wang, Ze; Ma, Hong; Sun, Yinghui; Ci, Xiaoyan; Gu, Yuan; Liu, Changxiao; Si, Duanyun
• Is Part Of: Pharmaceutical biology. Volume 59:Number 1(2021)
• Page Start: 198
• Page End: 206
• Publication Date: 2021-01-01
• Subjects: Drug–drug interaction -- CYP3A -- P-gp -- oral bioavailability; Pharmacognosy -- Periodicals; Materia medica, Vegetable -- Periodicals; 615.321
• DOI: 10.1080/13880209.2021.1871634
• Languages: English
• ISSNs: 1388-0209

Abstract

Abstract: 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.