Evaluation of Pharmacokinetic Interaction between Metformin and Berberine in Rats
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Metformin (MET) is the first line anti-diabetic drug for type 2 diabetes mellitus. Berberine (BBR) is the active ingredient of the Chinese herbs Coptidis Rhizoma, which has been used in the treatment of diabetes for more than a thousand years. Although MET and BBR have been proven to be effective as anti-diabetic treatments separately, their potential pharmacokinetic interactions have only been studied after intravenous (i.v.) injection without any data after oral route of administration. To address this knowledge gap, the current study aimed to investigate the pharmacokinetic interactions of MET and BBR in rats after oral administration.
Male Sprague-Dawley (SD) rats (200-220g) were randomly divided into two groups (G1: MET only group, G2: MET+BBR group). Rats from G1 received a single dose of MET at 200 mg/kg/body weight (in purified water, human equivalent dose). Rats from G2 first received the same MET (200 mg/kg/body weight, in purified water) dose. Then, after 2-hour post-dose of MET, BBR (200 mg/kg/body weight, in 0.5% CMC-Na, human equivalent dose) were given via gavage. All SD rats went through jugular vein cannulation surgery one day before dose administration. Before and after dosing, 200 μL of blood samples were drawn through a jugular vein catheter at 15, 30 min, 1, 2, 2.5, 3, 3.5, 4, 5, 7, 9, 12 and 24 hour post-dosing MET. To 100 µL plasma sample, 50 µL albuterol sulfate (ALB, IS for MET, 250 ng/ml), 50 µL caffeine (CAF, IS for BBR, 1000 ng/ml) and 200 µL methanol were added for protein precipitation. Then, 300 µL supernatant were collected for N2 drying. Samples were reconstituted with 50 µL 0.2% formic acid and 50 µL acetonitrile after N2 drying. The mixture was vortex mixed for 20 seconds. After centrifugation at 13, 200 rpm for 15 min, the supernatants were collected. Concentrations of MET and BBR in plasma were analyzed by validated LC/MS/MS (Liquid Chromatography–Tandem Mass Spectrometry) methods. The liquid chromatographic separation was carried out on a SunFireTM C8 (4.6×250 mm, 5 μm) analytical column. For detecting plasma MET concentration, quantification was carried out using selected reaction monitoring m/z 130.1 → 60.1 for MET and m/z 240.0 → 148.0 for ALB. The mobile phase consisted of acetonitrile (ACN) and water (20:80, v/v) at a flow rate of 0.8 ml/min. For detecting BBR concentration in plasma, quantification was carried out using selected reaction monitoring m/z 336.1→320.1 for BBR and 195.1→138.0 for CAF. The total analysis time was 11 min and a gradient condition was used as follows (time, % of ACN): 0.00-3.00 min, 10~30% ACN; 3.00-7.50 min, 30~10% ACN; 7.50-8.00 min, 10% ACN; 8.00-11.00 min, 10% ACN.
Plasma concentration of both MET and BBR provided satisfied linearity (r2>0.99). The linear range of MET and BBR concentration in plasma was 80-40000 ng/ml and 1-250 ng/ml, respectively. After oral administration of BBR and MET, BBR concentration in both G1 and G2 depicted in a low level below the LLOQ (Lower Limit of Quantification) of our assay. The Cmax of BBR in two groups were less than 15 ng/ml, which did not show any significant difference. However, it was found that BBR had an impact on the pharmacokinetics of MET. Although the Tmax, Cmax and t1/2 of MET did not suggest any significant difference between G1 and G2, co-administration with BBR increased the AUC0-∞ of MET from 4.9±0.5 min·mg/ml to 12.6±6.6 min·mg/ml and reduced the Clearance (CL) of MET by about 50% from 41±4 ml/min/kg in rats receiving MET alone compared to 19±10 ml/min/kg in rats receiving both MET and BBR (p<0.05).
Our results have demonstrated that co-administration of BBR with MET after oral route leads to increased AUC0-∞ value and decreased CL value of MET. This could possibly be due to the potential effect of BBR in decreasing the hepatic uptake and/or renal elimination of MET[1].
[1] Kwon M, Choi YA, Choi MK, Song IS. Organic cation transporter-mediated drug–drug interaction potential between berberine and metformin. Arch Pharm Res. 2015;38:849–856.
Acceptance Date19/07/2018
All Author(s) ListYuanfeng Lyu, Yufeng Zhang, Mengbi Yang, Alice Pik Shan Kong, Zhong Zuo
Name of ConferenceAmerican Association of Pharmaceutical Scientists (AAPS) 2018 PharmSci 360
Start Date of Conference04/11/2018
End Date of Conference07/11/2018
Place of ConferenceWashington DC, U.S.A.
Country/Region of ConferenceUnited States of America
LanguagesEnglish-United States

Last updated on 2019-02-10 at 09:30