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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 (CL z ) 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 t 1/2  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−∞)  of Rh123 ( p  < 0.001), meanwhile raise C max  of Rh123 and shorten its V z  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.

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