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.
Highlights
Cytochrome P450 are important drug metabolism enzymes in vivo, involved in the metabolism of some important endogenous substances and more than 50 % of the clinical medicine
We studied the effects of berberine hydrochloride (BBR) on MDZ and rhodamine 123 (Rh123) metabolism in rats to evaluate the effects of BBR on cytochrome p450 3A (CYP3A) activity and P-gp transporter
We studied the influence of BBR on pharmacokinetics of MDZ and Rh123, which acts as the probes of CYP3A and P-gp respectively
Summary
Animals Pharmacokinetic study Healthy male Sprague–Dawley rats, weighing 250–280 g and 2–3 months of age, were purchased from Laboratory Animal Research Center of Wuhan University (Wuhan, China). The rats in the treated groups were administrated in the same way for 10 consecutive days, and rats were gavaged with equal volume of verapamil (4 mg/kg) in the positive control group. 30 min after the rats were treated with their respective drugs, Rh123 (5 mg/kg) was orally administrated. Blood samples were drawn from the caudal vein at 0, 5, 10, 20, 30, 60, 90 min and 3, 6, 9, 12, 18, 24, 36, 48 h after administration of Rho123, the samples were immediately heparinized and plasma samples were obtained, which were frozen at −40 °C until HPLC analysis. The mobile phase consisted of acetonitrile and 20 mM phosphate buffer (pH = 4.0) (60:40, v/v) and was pumped at a constant rate of 1.0 ml/ min.
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