The Effect of Ethyl Acetate Extract of Pomelo Mix on Systemic Exposure of Verapamil in Rabbits

Suad      M. Aqel; Yacoub      M. Irshaid; Munir      N. Gharaibeh; Tawfiq      A. Arafat

Abstract

The effect of ethyl acetate extract of pomelo fruit on systemic exposure of verapamil was explored in rabbits. Two groups each of 8 locally-inbred New Zealand male rabbits were used. The first group was used for single-dose treatment (both verapamil and pomelo extract). The second group was used for multiple-dose treatment, pomelo extract (once daily for 14 days) and verapamil single doses (at days 7 and 14). A verapamil dose of 30 mg/kg and a pomelo extract dose of 45 mg/kg were used.

Single-dose treatment with pomelo extract resulted in a minor change in mean Cmax of verapamil in plasma, while a decrease of 37.8% in AUC0-24 and 28.3% in AUC_0-∞ was observed but did not reach statistical significance. After the first period of multiple dose treatment (pomelo extract for 7 days), the combination increased the concentration of verapamil in plasma with a significant increase in mean Cmax, AUC0-24 and AUC_0-∞ by 461.9%, 299.7%, and 261.1%, respectively (p values were 0.005, 0.002, and 0.006, respectively). In contrast, after the second period (day 14 of pomelo extract use), the combination decreased the concentration of verapamil in the plasma with a substantial decrease in mean Cmax, AUC0-24, and AUC_0-∞, by 68.2%, 69.7% and 58.3%, respectively. This decrease did not reach statistical significance (p values were 0.073, 0.081 and 0.083, respectively). The Tmax was not affected significantly in both studies. The study illustrates a complex time-dependent interaction between verapamil and the ethyl acetate extract of pomelo mix. More intensive studies are needed to further understand the nature of the interaction.

Keywords: Pharmacokinetics, Pomelo, Rabbits, Systemic exposure, Verapamil, CYP3A4, ischemic heart disease, hypertension, P-glycoprotein (P-gp), cyclosporine A