RESUMO
This study aimed to evaluate the effects of Jiawei Foshou San capsule (JWFSSC) on CYP1A2, CYP2C6, CYP2D2, CYP2E1 and CYP3A1/2 enzyme activities in rat liver microsomes in vitro and in vivo, and to provide pharmacokinetic data for its combined use with other medicines. After incubating liver microsomes with a cocktail of probe drugs, the metabolites were quantitated with LC-MS/MS to assess the CYP enzyme activity. The hepatic pathological changes were evaluated by histology after hematoxylin and eosin (HE) staining. With the dose range up to 3 200 mg·L-1, the IC50 of JWFSSC for CYP2D2, CYP2E1 and CYP3A1/2 in vitro was 229.3 mg·L-1, 361.9 mg·L-1 and 274.6 mg·L-1 respectively. Compared with the vehicle control group, the enzyme activities of CYP1A2, CYP2C6 and CYP3A1/2 showed a significant increase in animals given JWFSSC 180 mg·kg-1·d-1 (P<0.01). Based on histology, several pathological changes were observed in JWFSSC groups: there was less inflammatory infiltration compared to the tetrahydropalmatine (THP) group. These results of inhibition in vitro and induction in vivo suggest a strengthened efficacy and a prolonged effective time of drugs metabolized by CYP2D2 and CYP2E1 enzymes when combined with JWFSSC in use. The dosage of parent drugs should be appropriately reduced when used in combination with JWFSSC. However, if a drug is metabolized by CYP1A2 and CYP2C6 when used in combination with JWFSSC, the effect of the drug is likely reduced and the dosage should be increased appropriately. In addition, the combination of ferulic acid (FA), ligustrazine (LZ) and THP can significantly reduce the toxicity of THP in rat livers. In this study, the program of animal testing had been approved by Committee on the management and usage of experimental animal in the College of Pharmaceutical Sciences, Southwest University.
RESUMO
This study was designed to investigate the inhibitory effects of Jiawei Foshou San (JWFSS) capsule in vitro on five major human liver microsomes CYP1A2, CYP2C9, CYP2D6, CYP2E1, CYP3A4, as well as on rat liver microsomes CYP1A2, CYP2C9, CYP2D2, CYP2E1, CYP3A1/2. The test groups included a negative control group, an inhibitor positive control group, an ferulic acid (FA) group, a ligustrazine (LZ) group, a tetrahydropalmatine (THP) group, and an JWFSS capsule group. After incubating the liver microsomes with a cocktail of probe drugs, the metabolites were quantitated with LC-MS/MS, and IC 50 values were calculated to assess the inhibitory effect of JWFSS capsule and its components on five rat/human CYP450 enzymes. All of the IC50 values for the FA and the LZ for the five CYPs could not be determined. The IC50 of the THP for rat CYP3A1/2 and for human CYP2D6 was 7.46 and 9.24 μmol·L-1, respectively. The IC50 of the JWFSS capsule for rat CYP2D2, CYP2E1 and CYP3A1/2 was 241.3, 369.8 and 293.0 mg ·L-1, for human CYP2D6, CYP2E1 and CYP3A4 was 123.9, 189.9 and 171.3 mg·L-1 respectively. The results indicated there were little probability that FA and LZ inhibited the activity of rat and human liver five CYPs; THP was identified as moderate-intensity inhibitor of rat liver CYP3A1/2 and human liver CYP2D6; JWFSS capsule might have a inhibitory effect on the activity of rat and human liver CYP2D, CYP2E1 and CYP3A in vitro, showing that there was a strengthened efficacy and a prolonged effective time for drugs metabolized by CYP2D, CYP2E1, CYP3A and combined with JWFSS capsule.
