Effects of berberine on the pharmacokinetics of losartan and its metabolite EXP3174 in rats and its mechanism.

CONTEXT: Losartan and berberine (BBR) are often simultaneously used for the treatment of senile diabetic nephropathy in clinics. However, the potential herb-drug interaction between losartan and BBR is unknown.

OBJECTIVE: This study investigates the influence of BBR on the pharmacokinetics of losartan and EXP3174, and investigates the effects of BBR on the metabolic stability of losartan.

MATERIALS AND METHODS: The pharmacokinetic profiles losartan and EXP3174 of orally administered losartan (10 mg/kg) with and without pretreatment with BBR (20 mg/kg) within 24 h were determined in Sprague-Dawley rats. The inhibitory effects of BBR on the metabolic stability of losartan were investigated using rat liver microsomes.

RESULTS: The Cmax (1.26 ± 0.37 versus 1.96 ± 0.45 mg/L) and the AUC(0-t) (8.25 ± 0.89 versus 12.70 ± 1.42 mg h/L) of losartan were significantly (p < 0.05) increased by BBR compared to the control, while the Cmax (0.97 ± 0.15 versus 0.77 ± 0.06 mg/L) of EXP3174 was significantly decreased compared to the control (p < 0.05). The Tmax of losartan was prolonged from 0.41 ± 0.12 to 0.52 ± 0.18 h, but the difference was not significant. However, the Tmax of EXP3174 was decreased significantly (p < 0.05) from 8.14 ± 0.36 to 3.33 ± 0.28 h. The metabolic stability of losartan was increased from 37.4 to 59.6 min.

DISCUSSION AND CONCLUSION: We infer that BBR might increase the plasma concentration of losartan and decrease the concentration of EXP3174 through inhibiting the activity of CYP3A4 or CYP2C9.