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

Abstract

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.MethodsThe 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.ResultsBBR 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).ConclusionThe 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.

Dual‐Stimuli‐Responsive Gut Microbiota‐Targeting Berberine‐CS/PT‐NPs Improved Metabolic Status in Obese Hamsters

“…This result demonstrated that efflux transporters were involved in the transepithelial transport of Rho 123. After exposure to the BBR solution (BBR‐S, 100 × 10 −6 m ), the P app (A‐B) of Rho123 increased to 3.76 ± 0.51 × 10 −6 cm s −1 , and P app (B‐A) transportation decreased to 7.22 ± 0.49 × 10 −6 cm s −1 , which agreed with previous research that BBR could increase the absorption of Rho123 via the competitive inhibition of P‐gp . In contrast, no significant difference was detected by the addition of BBR‐CS/PT‐NPs (100 × 10 −6 m of BBR).…”

Comparative pharmacokinetics and safety assessment of transdermal berberine and dihydroberberine

“…Simvastatin and berberine both undergo metabolism in the liver primarily through CYP3A4 [ 44 , 49 ]. Furthermore, Liu et.…”

The Quest to Enhance the Efficacy of Berberine for Type-2 Diabetes and Associated Diseases: Physicochemical Modification Approaches

“…The metabolism parameters of lovastatin such as clearance (CL), maximum rate (V max ) and Michaelis constant (K m ) increased after treatment with berberine. Xin et al [58] also studied the effects of berberine on the pharmacokinetics of midazolam and rhodamine 123 in rats. They showed that berberine could increase the C max of midazolam while reducing its clearance rate and the volume of the distribution of midazolam.…”