Goldenseal (Hydrastis canadensis)
In Vivo and in Vitro Study on Drug-Drug Interaction of Lovastatin and Berberine from Pharmacokinetic and HepG2 Cell Metabolism Studies CSV JSON

Background: We assumed that the pharmacokinetics of lovastatin could be changed by the induction effect of berberine.

Methods: An UPLC-MS/MS method was developed and validated for the pharmacokinetics tudy of lovastatin to investigate the in vivo drug-drug interactions between lovastatin and berberine. SD male rats were random divided into lovastatin group and berberine induced prior to lovastatin group for the in vivo pharmacokinetic studies. Meanwhile HepG2 cells were induced by berberine for three days to study the metabolism of lovastatin.

Results: The AUC (p < 0.01) and Cmax (p < 0.01) could be significantly decreased in the berberine-induced groupin vivo, and the metabolic activity of HepG2 cell ccould be increased by berberine induction in vitro. The metabolism parameters of lovastatin such as CL, Vmax and Km were increased after the induction of berberine. From the pharmacokinetic study of lovastatin induced with berberine, we obtained pharmacokinetic parameters which are compliance with the metabolic parameters of lovastatin in HepG2 cells with berberine induction in vitro.

Conclusions: From the in vivo pharmacokinetics study and the HepG2 cell metabolism study in vitro, berberine could be an inducer for the metabolism of lovastatin according to our previous research on berberine induction effects on HepG2 cells, which may be relevant to the fact that berberine possesses induction effects through the CYP 450 3A4 enzyme.

PMID: 27070564


1 . Induction of CYP3A4 by Berberine (id=NPDI-K4rJHw)

In Vitro Enzyme Induction Experiment

Induction was detected.  Cutoff used — not specified


  • CYP3A4 4306811

Cell system HepG2 cell line


Sample Compound measured Value Measurement Study sequence Additional information N replicates

Experimental Conditions

To investigate the induction effect of BER on HepG2 cells, 200 μL of 1 x10^6/mL HepG2 cell suspension was placed in a 6-well plate and incubated with 2 mL of culturemedium for 4 days (culture medium was replaced every 2 days). When the cell fusion was approximately 90%, the medium was discarded, and 2 mL of BER (1.0 μg̈ mĹ1 prepared in culture medium) was added into three wells, and 2 mL of drug-free culture medium was added into the other three wells. After incubation for three days, the medium was discarded, 2 mL of lovastatin (1.0 μg̈ mĹ1 prepared in culture medium) was added into each well prior to incubation for 90 min, then 100 μL of the sample were collected at 0, 30, 60 and 90 min, the sample was added with 50 μL ofice-cold sodium acetate buffer (100 mM; pH 4.5 at room temperature) prior to addition of 150 μL cool acetonitrile (containing 100 ng̈ mĹ1 warfarin as internal standard, 4 ̋C), then vortexed for 2 min and centrifuged at 13,500 x g for 15 min, the supernatant was placed into a 96-well polypropylene plate for analysis, where the sodium acetate buffer was used to protect the transformation of lovastatin and lovastatin acid [39]. The linearity for the analysis of lovastatin was determined with 100 μL of blank samples (200 μL of HepG2 cell suspension added with 2 mL culture medium) added with 50 μL of ice-cold sodium acetate buffer (100 mM; pH 4.5 at room temperature) and 150 μL cool acetonitrile (containing 100 ng̈ mĹ1 warfarin as internal standard, 4 ̋C) prepared at final concentrations levels of 10, 25, 50, 100, 250 and 500 ng̈ mĹ1, QC samples were prepared at final concentrations of 30, 75, 150, 300 ng̈ mĹ1 as the sample preparation. The UPLC-MS/MS analysis was performed as well as determination of lovastatin acid. MS/MS condition transitions (m/z) for lovastatin were 405.35Ñ285.22, the parameters of cone voltage and collision energy were 16 and 12 V, respectively.

Enzyme activity

1x10^6 cells/mL

2.0 μg

90 m