Effects of berberine on pharmacokinetics of midazolam and rhodamine 123 in rats in vivo

Aim: To evaluate whether berberine hydrochloride (BBR) could modify the pharmacokinetic profiles of midazolam (MDZ), a substrate of CYP3A, and rhodamine 123 (Rh123), a substrate of P-glycolprotein (P-gp), in male rats. Methods: The rats were given with varied does of BBR or 75 mg/kg ketoconazole as a positive control for 10 days by intragastric administration. Single-pass duodenum perfusion of 20 mg/kg MDZ and inguinal artery canulated rats were used in the study. Plasma concentrations of MDZ and 1'-hydroxymidazolam (1'-OH-MDZ) were analyzed by high performance liquid chromatography (HPLC). The rats were given with varied does of BBR or 4 mg/kg verapamil as a positive control for 10 days by intragastric administration. Blood was obtained from the caudal vein of rats after single-pass intragastric administration of 5 mg/kg Rh123. HPLC was used to analyze the plasma concentrations of Rh123. Results: BBR produced similar results as the ketoconazole (positive control group) with a dose-dependent increase in the AUC((0-t)) and AUMC((0-t)) of midazolam except at the dose of 50 mg/kg (p < 0.01). And BBR could significantly increase the peak plasma concentrations (C-max) of MDZ (p < 0.01), but reduce the clearance rate (CLz) and the apparent volume of the distribution (V-z) of MDZ (p < 0.05). The results also indicated that BBR had no significant impact on the half-life period (t(1/2)) and the time to reach peak concentration (t(max)). Meanwhile, BBR could dose-dependently decrease AUC((0-t)) and AUMC((0-t)) of 1'-OH-MDZ significantly (p < 0.05), and expedite the clearance rate of 1'-OH-MDZ while gaining its apparent volume of distribution (p < 0.05), but had no significant impact on t1/2 and T-max. The result also showed that BBR, except at the dose of 50 mg/kg, and the positive verapamil group could significantly increase the AUC((0-t)) and AUC((0-infinity)) of Rh123 (p < 0.001), meanwhile raise C-max of Rh123 and shorten its Vz inversely (p < 0.05). Additionally, pre-treatment with BBR had no significant influence with the half-life period of Rh123, while significantly reduced its clearance rate (p < 0.05). Conclusion: The metabolism of MDZ and Rh123 was controlled by BBR. The results were most likely due to the inhibition by BBR on CYP3A enzymes and P-gp transporter.