| Purpose:The aim of this study was to investigate the effect of breviscapine on the pharmacokinetics of simvastatin, and the co-administration of breviscapine and simvastatin affected drug metabolism activity. From the perspective of drug metabolizing enzymes, the reveal affected breviscapine on the pharmacokinetics mechanism of simvastatin. Rational use of the two drugs provided some experimental basis in clinical, and further suggested breviscapine interact with other CYP3A4 substrate drug. To guide the rational use of drugs in clinical and provide the scientific evidence.Methods:Rats were randomly divided into simvastatin (40mg/kg,i.g) group and simvastatin combined with breviscapine(20mg/kg,i. v) intravenous injection group. Blood samples were collected in different time point before and after administration drug, and processed all the plasma sample. The levels of simvastatin in plasma was measured using the high performance liquid chromatography (HPLC) method, draw blood concentration-time curve. The pharmacokinetic parameters was calculated with application software 3P97 pharmacokinetic. The chromatographic separation were completed on a reversed-phase C18 column using acetonitrile-0.15% aqueous acetic acid(64:36, v/v) as mobile phase at a flow rate of 1 ml-min-1 and ultraviolet detection wave length was set at 233 nm and the column temperature was 25 ℃. Rats were divided into four groups: control group, simvastatin alone group, breviscapine alone group, simvastatin combined with breviscapine group, respectively. Each group continuously administered once a day for seven days. The control group received physiological water, the eighth day took hepatic microsomal liver preparation. The content of CYP450 in liver cells of rats were determined with UV spectrophotometer and fluorescence spectrophotometry, and extracted RNA in the liver cell with reverse transcription polymerase chain reaction (RT-PCR)determination influence of drugs on liver enzyme CYP3A4 gene expression.Results:(1)Effect of breviscapine on simvastatin pharmacokinetics in ratsCompared with simvastatin group, the pharmacokinetic parameters of simvastatin increased the maximum of plasma concentration, significantly reduced clearance, significantly prolonged the mean residence time, and significantly increased mean plasma concentration time curve in simvastatin combined with breviscapine group.(2) Effect of breviscapine combined with simvastatin on CYP450 enzyme activity and enzyme soform gene expression in ratsCompared with saline group, the protein content of CYP450 and CYP3A4 enzyme gene expression did not significantly change in simvastatin group, and the protein content of CYP450 decreased in breviscapine group and breviscapine combined with simvastatin group, which enzyme activity significantly inhibited in breviscapine combined with simvastatin group. Breviscapine group and Breviscapine combined with simvastatin group reduced the CYP3A4mRNA expression level(P<0.05), but two data did not significant difference compared with saline group.Conclusions:Breviscapine reduced hepatic microsomal CYP450 enzyme content and CYP3A4 gene expression, and inhibited metabolic activity of CYP3A4 enzyme, meanwhile, simvastatin, which is enzyme substrate, reduced the extent of metabolism in vivo and pharmacokinetic study results that plasma concentration of simvastatin increased and residence time prolonged, were consistent.Therefore, breviscapine reduced the side effects of simvastatin reason that was breviscapine inhibited the metabolism of simvastatin drug-metabolizing enzyme activity of CYP3A4 and reduced simvastatin metabolism, and further enhanced simvastatin’s efficacy. |
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