Calycosin Influences the Metabolism of Five Probe Drugs in Rats.

BACKGROUND: Calycosin (CAL), a type of O-methylated isoflavone extracted from the herb Astralagusmembranaceus (AM), is a bioactive chemical with antioxidative, antiphlogistic and antineoplastic activities commonly used in traditional alternative Chinese medicine. AM has been shown to confer health benefits as an adjuvant in the treatment of a variety of diseases. AIM: The main objective of this study was to determine whether CAL influences the cytochrome P450 (CYP450) system involved in drug metabolism. METHODS: Midazolam, tolbutamide, omeprazole, metoprolol and phenacetin were selected as probe drugs. Rats were randomly divided into three groups, specifically, 5% Carboxymethyl cellulose (CMC) for 8 days (Control), 5% CMC for 7 days + CAL for 1 day (single CAL) and CAL for 8 days (conc CAL), and metabolism of the five probe drugs evaluated using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). RESULTS: No significant differences were observed for omeprazole and midazolam, compared to the control group. T max and t1/2 values of only one probe drug, phenacetin, in the conc CAL group were significantly different from those of the control group (T max h: 0.50±0.00 vs 0.23±0.15; control vs conc CAL). C max of tolbutamide was decreased about two-fold in the conc CAL treatment group (conc vs control: 219.48 vs 429.56, P<0.001). CONCLUSION: Calycosin inhibits the catalytic activities of CYP1A2, CYP2D6 and CYP2C9. Accordingly, we recommend caution, particularly when combining CAL as a modality therapy with drugs metabolized by CYP1A2, CYP2D6 and CYP2C9, to reduce the potential risks of drug accumulation or ineffective treatment.

Effects of salidroside on rat CYP enzymes by a cocktail of probe drugs.

OBJECTIVES: In this study, we aimed to evaluate the effect of salidroside on the activities of the different drug-metabolizing enzymes CYP1A2, CYP2B6, CYP2C9, CYP2D6 and CYP3A4 in rats, in which a specific probe drug was used for each enzyme. MATERIALS AND METHODS: After pretreatment with salidroside, five probe drugs were simultaneously administered to rats by gavage. The given dose was 2.0 mg/kg for phenacetin (CYP1A2 activity), 4.0 mg/kg for bupropion (CYP2B6 activity), 2.0 mg/kg for losartan (CYP2C9 activity), 8.0 mg/kg for metoprolol (CYP2D6 activity) and 1.0 mg/kg for midazolam (CYP3A4 activity). Then, an ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was used to analyze the concentrations of rats' blood, which were collected at different corresponding times. RESULTS: Our data showed that salidroside exhibited an inductive effect on CYP1A2, CYP2B6, CYP2C9 and CYP3A4 activities by changing the main pharmacokinetic parameters (t1/2, CL/F, Cmax and AUC(0-∞)) of the four probe drugs in rats. However, no significant changes in CYP2D6 activity were observed. CONCLUSION: In a word, the results displayed that salidroside could induce the activities of CYP1A2, CYP2B6, CYP2C9 and CYP3A4, which may influence the disposition of the drugs that are mainly metabolized by these pathways. Our research can provide the basis for the study of related herb-drug interactions in clinic.

[Effect of Bugu Mixture on all-trans retinoic acid-induced apoptosis of bone marrow stromal cells].

OBJECTIVE: We used the SD rat's bone marrow stromal cells (BMSCs) cultured in vitro to observe the effects of Bugu Mixture on the apoptosis and to explore the molecular biologic mechanism of the treatment of osteoporosis with Bugu Mixture. METHODS: BMSCs were separated from the bones of the extremities of SD rats in vitro. The morphologic changes, the apoptosis cell cycles, the mitochondrion membrane potential changes, and the Bcl-2 and Bax gene expression were observed, and the effects of Bugu Mixture on the course of cell apoptosis were evaluated. RESULTS: The earlier use of Bugu Mixture could decrease the cells blocked in G0/G1 phase, and promote their synthesis of DNA in S phase. The expression of Bcl-2 was higher in the Bugu Mixture group than that in the all-trans retinoic acid (ATRA) induced group, and the expression of Bax was lower in the Bugu Mixture group than that in the ATRA induced group. The mitochondrion membrane potential descended significantly in the Bugu Mixture group than that in the ATRA induced group. CONCLUSION: The mechanism of the treatment of osteoporosis with Bugu Mixture is that the earlier use of Bugu Mixture can decrease the amount of apoptostic cells induced by ATRA, thus promoting the cell mitosis and restraining the apoptosis. It can also act as a protector to Bcl-2 located on the mitochondrion membrane. By preventing the transferring of the Bax protein from cell-plasma to mitochondrion membrane, it takes the advantage of Bcl-2 in forming Bcl-2/Bax homodimer so as to prevent the opening of the permeability transition pore to avoid the changing of mitochondrion membrane potential and the destruction of biosynthesis caused by the mitochondrion release of apoptosis inducing factors and to reach the objective of restraining apoptosis.