title: Effects of berberine on pharmacokinetics of midazolam and rhodamine 123 in rats in vivo.
abstract: OBJECTIVE
  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 (Cmax) of MDZ (p < 0.01), but reduce the clearance rate (CLz) and the apparent volume of the distribution (Vz) of MDZ (p < 0.05). The results also indicated that BBR had no significant impact on the half-life period (t1/2) and the time to reach peak concentration (tmax). 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 Tmax. 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 Cmax 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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Clinical Pharmacology, Wuhan General Hospital of Guangzhou Command, Wuhan, 430070 China.
authors.forename: Hua-Wen
authors.initials: HW
authors.lastname: Xin
authors.affiliation: Department of Clinical Pharmacology, Wuhan General Hospital of Guangzhou Command, Wuhan, 430070 China.
authors.forename: Xia
authors.initials: X
authors.lastname: Tang
authors.affiliation: Department of Clinical Pharmacology, Wuhan General Hospital of Guangzhou Command, Wuhan, 430070 China.
authors.forename: Meng
authors.initials: M
authors.lastname: Ouyang
authors.affiliation: Department of Clinical Pharmacology, Wuhan General Hospital of Guangzhou Command, Wuhan, 430070 China.
authors.forename: Jian-Xun
authors.initials: JX
authors.lastname: Zhong
authors.affiliation: Department of Clinical Pharmacology, Wuhan General Hospital of Guangzhou Command, Wuhan, 430070 China.
authors.forename: Wei-Liang
authors.initials: WL
authors.lastname: Li
keywords: Berberine hydrochloride; CYP3A; Midazolam; P-glycolprotein; Pharmacokinetics; Rhodamine 123